Journal of Experimental Botany, Vol. 54, No. 382, pp. 595-604,
January 1, 2003
© 2003 Oxford University Press
Function and specificity of 14-3-3 proteins in the regulation of carbohydrate and nitrogen metabolism
Received 13 September 2002; Accepted 26 September 2002
University of Cambridge, Department of Plant Sciences, Downing Site, Cambridge CB2 3EA, UK
1 To whom correspondence should be addressed. Fax: +44 (0)1223 333953. E-mail: trm23{at}cam.ac.uk
Abbreviations: AICAR, 5-aminoimidazole-4-carboxamide riboside; GS, glutamine synthetase; NIP, nitrate reductase inhibitor protein; NR, nitrate reductase; PM, plasma membrane; SPS, sucrose-phosphate synthase.
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Abstract |
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 Top Abstract Introduction14-3-3 proteins in plants14-3-3 proteins regulate plant...14-3-3 proteins regulate key...Interaction of 14-3-3 proteins...14-3-3 proteins interact with...14-3-3 proteins bind to...Structure, function, modulationRegulation and localization of...Conclusion and perspectivesReferences |
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Protein phosphorylation is key to the regulation of many proteins. Altered protein activity often requires the interaction of the phosphorylated protein with a class of ‘adapters’ known as 14-3-3 proteins. This review will cover aspects of 14-3-3 interaction with key proteins of carbon and nitrogen metabolism such as nitrate reductase, glutamine synthetase and sucrose-phosphate synthase. It will also address 14-3-3 involvement in signal transduction pathways with emphasis on the regulation of plant metabolism. To date, 14-3-3 proteins have been identified and studied in many diverse systems, yielding a plethora of data, requiring careful analysis and interpretation. Problems such as these are not uncommon when dealing with multigene families. The number of isoforms makes the question of redundancy versus specificity of 14-3-3 proteins a crucial one. This issue is discussed in relation to structure, function and expression of 14-3-3 proteins.
Key words: ATPase, C/N metabolism, metabolic signalling, multigene family, nitrate reductase, 14-3-3 proteins, regulation, sucrose-phosphate synthase.
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Introduction |
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TopAbstractIntroduction14-3-3 proteins in plants14-3-3 proteins regulate plant...14-3-3 proteins regulate key...Interaction of 14-3-3 proteins...14-3-3 proteins interact with...14-3-3 proteins bind to...Structure, function, modulationRegulation and localization of...Conclusion and perspectivesReferences |
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14-3-3 proteins were first identified as abundant, acidic, soluble brain proteins with a molecular weight of 25– 32 kDa (Moore and Perez, 1967). Their enigmatic name was assigned according to fractionation on DEAE cellulose and electrophoretic mobility on starch gel electrophoresis during the purification of a number of bovine brain proteins of unknown function. Currently, individual members of 14-3-3 proteins are mostly designated by Greek letters. Arabidopsis 14-3-3 proteins are also named General Regulatory Factors (GRFs) thus taking into account that these proteins regulate a great number of cellular processes (Rooney and Ferl, 1995, 1996).
Originally 14-3-3 proteins were thought to be found only in brain tissue. However, it became clear that 14-3-3 proteins belong to a family of proteins present in all the eukaryotic organisms investigated. A database analysis performed by Rosenquist et al. (2000) listed 153 isoforms in 48 different species. Since then the number of 14-3-3 proteins and 14-3-3 harbouring organisms has probably grown by an order of magnitude. The number of putative 14-3-3 encoding genes ranges from two in yeast to 15 in Arabidopsis (van Heusden et al., 1992, 1995; Rosenquist et al., 2001). 14-3-3 proteins exhibit a high degree of sequence similarity, even between species (Wang and Shakes, 1996). In Arabidopsis, the amino acid sequences of 14-3-3 proteins are between 60% and 92% conserved amongst the various isoforms whilst 14-3-3 encoding genes are up to 86% identical (Wu et al., 1997). 14-3-3 proteins mainly exist as saddle-shaped homo- or heterodimers in which a broad central groove is able to bind to target proteins. Thus, 14-3-3 proteins can function as ‘adapters’, leading specific target proteins to each other or to a specific location.
The first description of a possible biological function was suggested by Ichimura et al. (1987) who correlated the amino acid sequence of 14-3-3 proteins to tryptophan hydroxylase activators. Since then, 14-3-3 proteins have been shown to play diverse roles in many biological processes, such as the activation of protein kinase C (Toker et al., 1990), the stimulation of calcium-dependent exocytosis (Morgan and Burgoyne, 1992), involvement in mitochondrial and chloroplastic import (Alam et al., 1994; May and Soll, 2000), the regulation of proton pumping mechanisms via the plant plasma membrane H+-ATPase (Oecking et al., 1994), and of key plant metabolic enzymes (Bachmann et al., 1996a; Moorhead et al., 1996; Toroser et al., 1998).
Therefore, it appears that 14-3-3 proteins display a broad spectrum of activities, with a common feature being the interaction with other proteins as binding partners (Palmgren et al., 1998; Fu et al., 2000). Binding partners usually display a phosphorylated motif which is recognized by 14-3-3 proteins and forms part of the interacting domain. The most common motif identified so far is RSXpSXP (pS: phosphorylated serine, X: any amino acid) (Muslin et al., 1996). However, 14-3-3 proteins also bind to other phosphoserine peptide motifs (Yaffe et al., 1997) and binding might also occur to unphosphorylated ligands (Alam et al., 1994; Petosa et al., 1998; Masters et al., 1999).
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14-3-3 proteins in plants |
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TopAbstractIntroduction14-3-3 proteins in plants14-3-3 proteins regulate plant...14-3-3 proteins regulate key...Interaction of 14-3-3 proteins...14-3-3 proteins interact with...14-3-3 proteins bind to...Structure, function, modulationRegulation and localization of...Conclusion and perspectivesReferences |
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In plants, 14-3-3 proteins have been isolated from many species, including Arabidopsis (Lu et al., 1992), barley (Brandt et al., 1992), maize (de Vetten et al., 1992), spinach (Hirsch et al., 1992), tobacco (Piotrowski and Oecking, 1998), potato (Wilczynski et al., 1998), and tomato (Roberts and Bowles, 1999). The recent completion of the Arabidopsis genome project facilitated the identification of up to 15 putative 14-3-3 genes, of which 12 are also represented as EST or cDNA clones (Rosenquist et al., 2001). An exon-based alignment enabled Wu et al. (1997) to classify Arabidopsis 14-3-3 genes into two main groups; the epsilon group and the non-epsilon group. This delineation is observed in plants as well as in animals, indicating that this divergence of 14-3-3 proteins is ancient. The different isoforms display a very high conservation of amino acid sequences in the core region, with the N- and C-termini being the most divergent.
Piotrowski and Oecking (1998) proposed the existence of at least five different subgroups of 14-3-3 encoding genes in plants; four of those are possible results of early gene duplication and divergence, whilst the fifth group is specific for monocotyledonous plants.
As observed in other eukaryotic organisms, plant 14-3-3 proteins are involved in many crucial processes interacting with numerous proteins involved in various biological processes. Examples include proteins of the G-box binding complex (de Vetten et al., 1992; Lu et al., 1992), the transcription factors and activators EmBP1 and RSG (Schultz et al., 1998; Igarashi et al., 2001), the plasma membrane H+-ATPase (Oecking et al., 1994), enzymes of carbon and nitrogen metabolism (Bachmann et al., 1996a; Toroser et al., 1998; Moorhead et al., 1999; Sehnke et al., 2001), a lipoxygenase from barley (Holtman et al., 2000), a membrane-bound ascorbate peroxidase (Zhang et al., 1997), and a tomato outward-rectifying K+ channel (Booij et al., 1999).
The interaction of 14-3-3 proteins with a number of metabolic enzymes suggests their involvement in metabolic regulation. The impact of 14-3-3 proteins on metabolism can be seen in antisense and overexpression experiments. Overexpression of 14-3-3 proteins in potato disturbed sugar, catecholamine and lipid content, whilst a 14-3-3 antisense experiment influenced tuber starch content, nitrate reductase activity and amino acid composition (Prescha et al., 2001; Swiedrych et al, 2002).
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14-3-3 proteins regulate plant H+-ATPase and ion channel activity |
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TopAbstractIntroduction14-3-3 proteins in plants14-3-3 proteins regulate plant...14-3-3 proteins regulate key...Interaction of 14-3-3 proteins...14-3-3 proteins interact with...14-3-3 proteins bind to...Structure, function, modulationRegulation and localization of...Conclusion and perspectivesReferences |
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The interaction between the plasma membrane (PM) H+-ATPase, the fungal metabolite fusicoccin and 14-3-3 proteins has been extensively studied and is so far the best understood interaction of 14-3-3s and target proteins. The PM H+-ATPase is known to play crucial roles in the plant cell by generating a proton gradient, thereby providing the driving force for nutrient uptake, phloem loading, water movements, stomatal closure, and opening. Its activity is regulated by many environmental stimuli and hormones. It is now clearly established that activity is modulated by the displacement of an auto-inhibitory C-terminal domain (Sze et al., 1999). Fusicoccin, a phytotoxin, affects PM H+-ATPase-mediated processes such as stomatal opening and cell elongation, by irreversibly activating the PM H+-ATPase via interaction with the auto-inhibitory domain (de Boer, 1997). The involvement of 14-3-3 proteins in this process has been investigated in great detail. 14-3-3 protein dimers bind to the phosphorylated PM H+-ATPase and form a complex that activates the pump. In addition, binding of 14-3-3 proteins to the PM H+-ATPase generates a fusicoccin receptor. Binding of fusicoccin stabilizes the labile ATPase:14-3-3 complex and induces a strong and persistent activation of the ATPase in vivo (Korthout and de Boer, 1994; Oecking et al., 1997). Binding of 14-3-3 proteins to AHA2, the Arabidopsis plasma membrane H+-ATPase, occurs at the last 98 C-terminal amino acids (Jahn et al., 1997). In spinach, phosphothreonine-948 in the C-terminal end of the pump forms an integral part of the 14-3-3 binding motif (Olsson et al., 1998). Oecking and Hagemann (1999) also showed that the binding site for 14-3-3 dimers is located in the C-terminal autoinhibitory domain. Moreover, these authors demonstrated the absolute requirement of the C-terminus for the formation of a functional fusicoccin complex.
To summarize, the binding of 14-3-3 proteins to the autoinhibitory domain of the H+-ATPase is sufficient to lead to the formation of unstable complexes with high activity. However, it is the binding of fusicoccin that stabilizes the interaction between 14-3-3 proteins and the enzyme, thereby giving rise to the formation of stable complexes with high proton pumping activity.
The PM H+-ATPase is not the only membrane protein regulated by 14-3-3 proteins. Addition of 14-3-3 proteins during patch clamp activity measurements of a tomato potassium outward-rectifying channel increased the activity of the channel (Booij et al., 1999). The authors suggested that 14-3-3 proteins may recruit ‘sleepy’ channels and bring them to a voltage-activated state. In the same way, 14-3-3 proteins from Vicia faba are able to enhance K+ conductance in tobacco (Saalbach et al., 1997). These authors propose that the ion regulation is performed by modulating kinase activities or by direct binding of 14-3-3 proteins to the channels.
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14-3-3 proteins regulate key enzymes in the nitrogen assimilation pathway |
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TopAbstractIntroduction14-3-3 proteins in plants14-3-3 proteins regulate plant...14-3-3 proteins regulate key...Interaction of 14-3-3 proteins...14-3-3 proteins interact with...14-3-3 proteins bind to...Structure, function, modulationRegulation and localization of...Conclusion and perspectivesReferences |
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The electrochemical gradient generated by the H+-ATPase drives many metabolic processes, including nitrate uptake across the plasma membrane of root cells. Nitrogen assimilation is an important step in the metabolism of the whole plant and involves the reduction of nitrate to nitrite by nitrate reductase (NR) (Crawford, 1995). Coarse control of NR expression is exerted by light and metabolites such as nitrate and sucrose, demonstrating cross-talk of primary carbohydrate and nitrogen metabolism. In addition, nitrate reductase is subject to fine control via inactivation by phosphorylation. Phosphorylation occurs in the hinge 1 region of nitrate reductase, at Ser-534 in Arabidopsis and Ser-543 in spinach (Douglas et al., 1995; Su et al., 1996). However, phosphorylation of the enzyme alone does not induce the inactivation. The process is completed after reversible binding of a nitrate reductase inhibitor protein (NIP; Bachmann et al., 1995). Purification of NIP in the late 90s showed that it is composed of one or more 14-3-3 isoforms (Bachmann et al., 1996b). The amino acid sequence surrounding the phosphorylated serine residues resembles the mammalian 14-3-3:Raf-1 interaction site and experiments using a raf-derived peptide, including the 14-3-3 binding site, blocked NIP activity on NR. (Moorhead et al., 1996; Huber et al., 1996) Further evidence came from the analysis of mutated NR demonstrating the conditional requirement of Ser-534 in the hinge 1 region of Arabidopsis NR for binding of 14-3-3 proteins (Kanamaru et al., 1999). Lillo et al. (1997) compared nitrate reductases from various plant species and all showed a down-regulation by phosphorylation and binding of 14-3-3 upon light-to-dark transition.
As mentioned previously, 14-3-3 binding to target proteins is sequence specific. In spinach NR, the motif RTApSTP appears to be the sequence recognized and closely resembles the consensus 14-3-3 binding motif RSXpSXP (Bachmann et al., 1996a; Moorhead et al., 1996; Kaiser et al., 2002). In spinach, nitrate reductase kinase has been identified as a calmodulin-domain protein kinase able to phosphorylate the spinach enzyme at Ser-543 (Douglas et al., 1998). Interestingly, 14-3-3 binding to nitrate reductase not only inhibits NR activity but can also mark the enzyme for degradation (Weiner and Kaiser, 1999).
Therefore it appears that NR is highly regulated, firstly by the steady-state level of the enzyme protein (Lillo, 1994; Crawford, 1995; Campbell, 1996) and secondly by reversible protein phosphorylation (Huber et al., 1992, 1994; MacKintosh, 1992).
Glutamine synthetase (GS) also binds 14-3-3 proteins (Moorhead et al., 1999). Finnemann and Schjoerring (2000) studied Brassica napus GS1, a cytosolic enzyme active in senescing leaves. This phosphoprotein is regulated post-translationally by reversible phosphorylation catalysed by a protein kinase and a microcystin-sensitive serine/threonine protein phosphatase. The phosphorylation status of the enzyme changes during light-to-dark transition, is dependent on the ATP/AMP ratio in vitro (Kaiser and Spill, 1991) and thus affects degradation susceptibility. In young photosynthetically active leaves, the requirement for ATP decreases the ATP/AMP ratio, thereby reducing the phosphorylation of the GS1 pool. In darkness, respiration increases ATP production, thereby inducing an increase of the ATP/AMP ratio. This leads to an increase of GS1 phosphorylation. During senescence, the rate of photosynthesis is decreased while the respiration is maintained or increased (Krömer, 1995). The amount of phosphorylated GS1 consequently increases, thus possibly allowing the remobilization of nitrogen. Phosphorylated GS1 interacts with 14-3-3 proteins, and the highest activity is measured if GS1 is both phosphorylated and bound to 14-3-3 (Finnemann and Schjoerring, 2000). Riedel et al. (2001) also showed interaction of the tobacco chloroplastic GS isoform (GS2) with 14-3-3 proteins. Only GS2 strongly associated with 14-3-3 proteins was found to be catalytically active.
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Interaction of 14-3-3 proteins with enzymes of carbohydrate metabolism |
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TopAbstractIntroduction14-3-3 proteins in plants14-3-3 proteins regulate plant...14-3-3 proteins regulate key...Interaction of 14-3-3 proteins...14-3-3 proteins interact with...14-3-3 proteins bind to...Structure, function, modulationRegulation and localization of...Conclusion and perspectivesReferences |
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Not only do 14-3-3 proteins regulate enzymes of the nitrogen assimilation pathway and proteins involved in generating proton gradients which serve as the driving force for nutrient uptake, they also regulate the activity of enzymes involved in primary carbon metabolism. Sucrose-phosphate synthase (SPS) is a good example of this. SPS catalyses the conversion of UDP-glucose and fructose-6-phosphate to sucrose-6-phosphate, the second last step in sucrose biosynthesis. SPS is regulated by allosteric effectors and protein turnover (Huber and Huber, 1996). The enzyme has several putative phosphorylation sites which regulate its activity by 14-3-3 dependent and independent mechanisms. Non-14-3-3 events include phosphorylation of SPS on Ser-424 and Ser-158 which are thought to be responsible for light/dark modulation and osmotic stress activation of the enzyme (McMichael et al., 1993; Toroser and Huber, 1997). However, there is a site-specific regulatory interaction between 14-3-3 proteins and Ser-229 of spinach SPS which inhibits SPS activity (Toroser et al., 1998).
The interaction of 14-3-3s and target proteins can be reduced in vitro by 5'-AMP which interacts with 14-3-3s and directly reduces their binding to target ligands (Kaiser and Spill, 1991; Athwal et al., 1998b). It is noteworthy that there is evidence for an AMP binding site in a spinach 14-3-3 isoform. Thus 14-3-3 protein activity might also be under metabolic control (Athwal et al., 1998b). The effect of 5'-AMP can be mimicked in vivo using 5-aminoimidazole-4-carboxamide riboside (AICAR), a cell permeable precursor of the 5'-AMP analogue ZMP (5'-aminoimidazole-4-carboxamide ribonucleoside monophosphate). Addition of AICAR to leaf tissue in the dark, for example, led to activation of nitrate reductase and accumulation of ZMP in the tissue without changing the general phosphate metabolism (Huber and Kaiser, 1996). Using AICAR feeding prior to analysing SPS activity, Toroser et al. (1998) showed a reduced 14-3-3 binding to SPS leading to higher SPS activity in the dark. The effect of AICAR may suggest a metabolic control of SPS activity in vivo.
Moorhead et al. (1999) describe the effect of 14-3-3s on sucrose-phosphate synthase (SPS) activities plus trehalose-6-phosphate synthase (TPS) in cauliflower extracts. Using a phosphopeptide which competes with target proteins for 14-3-3 binding, the authors showed a slight activation of sucrose-phosphate synthase activity. Although the authors state that the assay mostly measures SPS activity, it has to be kept in mind that TPS might contribute to the increase in sucrose-phosphate synthase activity. Furthermore, the use of different plant material or analytical techniques by Toroser et al. (1998) and Moorhead et al. (1999) might explain, at least partially, the different effects of 14-3-3 proteins on SPS activity.
Further evidence for the regulation of carbohydrate metabolism by 14-3-3 proteins came from Sehnke et al. (2001) who showed that reduction of the 
-subgroup of Arabidopsis 14-3-3 proteins by antisense techniques, resulted in a 2–4-fold increase in leaf starch accumulation. Breakdown of starch in the dark was not affected and 14-3-3 proteins were found as internal intrinsic granule proteins. Interestingly, all members of the starch synthase III family contain the conserved 14-3-3 phosphoserine/threonine-binding motif (RYGSIP) making them putative targets for 14-3-3 action.
Far Western overlay experiments also indicated binding of 14-3-3 proteins to trehalose-6-phosphate synthase, glyceraldehyde-3-phosphate dehydrogenase and ATP synthase suggesting regulation of these enzymes by 14-3-3-mediated processes (Moorhead et al., 1999; Cotelle et al., 2000). Additionally, evidence for the interaction and regulation of mitochondrial and chloroplastic ATP synthases by 14-3-3 proteins was shown by Bunney et al. (2001).
The targeting and regulation of key enzymes of carbon and nitrogen metabolism by 14-3-3 proteins suggest a common 14-3-3 mediated mechanism in regulating and possibly co-ordinating the use and generation of metabolites in plants. It is worth noting that primary carbon and nitrogen metabolites can also be sensed, leading to physiological and developmental changes. For example, nitrogen appears to regulate root system morphology, partitioning of photosynthetic carbon, and flowering. Nitrate, in addition to its metabolic role, has been identified as a signalling molecule. Nitrate can induce the expression of genes encoding for proteins of nitrogen metabolism, such as NR, nitrite reductase, GS and nitrate transporters. On the other hand, nitrate is a crucial signal in the regulation of carbon metabolic genes as shown by nitrate repression of AGPS, encoding for the regulatory subunit of ADP-glucose pyrophosphorylase, a key enzyme of starch synthesis (Scheible et al., 1997).
At the same time, sugars act in a complementary manner to nitrogen. For example, they induce genes encoding for nitrate transporters, NR, GS, and they also stimulate NR activity (Koch, 1996; Jang and Sheen, 1997; Stitt, 1999). Thus, a cross-talk between the two pathways, which allows plants to optimize the use of available resources, can be speculated (Coruzzi and Zhou, 2001). Other forms of regulation involve the sensing of the carbohydrate to nitrogen (C:N) ratio. Indeed, it has been shown that the C:N ratio, rather than the carbohydrate status or the nitrate availability alone, significantly affects the growth and development of Arabidopsis seedlings (Martin et al., 2002). Finally, as noted above, plasma membrane H+-ATPase and K+ channel activities are necessary to provide the electrochemical gradient needed for the transport of many metabolites, including sugars and amino acids.
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14-3-3 proteins interact with proteins of signalling pathways |
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TopAbstractIntroduction14-3-3 proteins in plants14-3-3 proteins regulate plant...14-3-3 proteins regulate key...Interaction of 14-3-3 proteins...14-3-3 proteins interact with...14-3-3 proteins bind to...Structure, function, modulationRegulation and localization of...Conclusion and perspectivesReferences |
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Evidence for the involvement of 14-3-3 proteins in metabolic sensing/signalling pathways comes from nutrient starvation experiments (Cotelle et al., 2000). Binding of 14-3-3 proteins to target enzymes such as NR or SPS was lost upon sugar starvation or feeding with non-metabolizable glucose analogues in Arabidopsis cell cultures. Loss of 14-3-3 binding resulted in proteolytic degradation of 14-3-3 binding enzymes, suggesting that 14-3-3 proteins may participate in a nutrient sensing pathway controlling the stability of many target proteins. From the overall discussion above it is tempting to attribute a central role in the control of plant primary metabolism to 14-3-3 proteins.
In addition to the direct regulation of metabolism by 14-3-3 proteins via enzyme activation/inactivation, 14-3-3 proteins have been shown to interact with components of signalling pathways. For instance, 14-3-3 proteins modulate the activity of a number of protein kinases such as protein kinase C (Robinson et al., 1995) and the calcium-dependent protein kinase CPK-1 in Arabidopsis (Camoni et al., 1998). Ikeda et al. (2000) demonstrated that 14-3-3 proteins are able to bind to the autophosphorylated C-terminal region of WPK4, a wheat protein kinase related to the yeast metabolite signalling kinase SNF1. WPK4 expression itself is regulated by light, general nutrient deprivation and the plant hormone cytokinin (Sano and Youssefian, 1994). Additionally, WPK4 phosphorylates NR in the hinge 1 region prior to 14-3-3 binding (Ikeda et al., 2000).
Apart from interaction with protein kinases, 14-3-3 proteins interact with other components of signalling pathways, for example with RGS3, a negative regulator of the G-alpha subunits of heterotrimeric G proteins (Niu et al., 2002). Thus, 14-3-3 proteins may be involved in controlling regulation of G-protein signalling pathways.
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14-3-3 proteins bind to transcription factor complexes |
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TopAbstractIntroduction14-3-3 proteins in plants14-3-3 proteins regulate plant...14-3-3 proteins regulate key...Interaction of 14-3-3 proteins...14-3-3 proteins interact with...14-3-3 proteins bind to...Structure, function, modulationRegulation and localization of...Conclusion and perspectivesReferences |
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Nuclear localization of 14-3-3 proteins has been shown using immunological analysis and laser scanning confocal microscopy (Bihn et al., 1997). This localization is somehow puzzling as 14-3-3 proteins lack recognizable nuclear localization signals. However, 14-3-3 association with transcription factor complexes such as the G-box binding complex may account for their presence in nuclei (de Vetten et al., 1992). G-box elements are moderately conserved elements in many gene promoters including the anaerobic response element of ADH1 promoter in Arabidopsis and maize (DeLisle and Ferl, 1990; McKendree and Ferl, 1992), the promoter of a chalcone synthase gene (Faktor et al., 1996), and promoters of the CabE gene and of the RbcS gene family (Schindler and Cashmore, 1990; Giuliano et al., 1988). It is tempting to suggest that 14-3-3 proteins exert a second level of metabolic control via interaction with protein complexes regulating promoter activities via G-box elements, found in several metabolic genes. Interestingly, G-box elements have also been found in maize 14-3-3 genes (de Vetten and Ferl, 1994). This may indicate possible autoregulatory mechanisms of 14-3-3 gene expression.
14-3-3 proteins in plants also interact with components of other transcription factor components. For instance, 14-3-3 proteins interact with the site-specific DNA binding proteins EmBP1 and the tissue-specific regulatory factor VP1 (Schultz et al., 1998).
RSG (Repression of Shoot Growth) is a bZIP transcriptional activator regulating endogenous GA amounts through the control of GA biosynthetic enzyme expression. It has been described as a 14-3-3 binding partner (Igarashi et al., 2001). A mutated form of RSG, that is unable to interact with 14-3-3s, has a higher transcriptional activity than the wild-type protein. This might be explained by the predominant localization of the mutant form in the nucleus, whilst the wild-type protein is found throughout the cell. Thus 14-3-3 proteins seem to control the nuclear localization of a transcription factor, possibly restricting its activity to a limited number of cells during development and in a restricted time frame.
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Structure, function, modulation |
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TopAbstractIntroduction14-3-3 proteins in plants14-3-3 proteins regulate plant...14-3-3 proteins regulate key...Interaction of 14-3-3 proteins...14-3-3 proteins interact with...14-3-3 proteins bind to...Structure, function, modulationRegulation and localization of...Conclusion and perspectivesReferences |
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Animal 14-3-3 monomeric proteins consist of nine antiparallel helices organized into an N-terminal domain (four helices) and a C-terminal domain (five helices) (Liu et al., 1995). Dimerization in animal 14-3-3 proteins requires the first three helices in the N-terminal domain (Luo et al., 1995). Because of the high degree of conservation between plant and animal 14-3-3 proteins one could predict the presence of nine helices within plant 14-3-3s. However, plant 14-3-3 proteins show distinct differences to animal 14-3-3s. Firstly, in plants, dimerization relies only on the fourth helix, a significant difference between animal and plant forms (Abarca et al., 1999). Secondly, some plant 14-3-3 proteins possess an EF-hand-like motif in the C-terminal region indicating possible interactions with calcium.
The structure of 14-3-3 proteins has a key role in interactions with target proteins. A common binding site for target proteins is located in the box-1 region (helices 7 and 8) in the C-terminus. This box is common to all 14-3-3 isoforms. In animal systems binding specificity can be affected by only a few amino acid variations in box 1 or in regions closely adjacent to box 1 (Ichimura et al., 1997).
In both plants and yeast 14-3-3 proteins bind to their target proteins in a cation-stimulated manner. Calcium possibly interacts with helices 8 and 9 causing conformation changes of the protein (Athwal et al., 1998a). Activation of 14-3-3s by cations may be due to neutralization of negative charges associated with acidic residues in the loop involving helices 8 and 9 (Athwal and Huber, 2002). Furthermore, calcium decreases the homodimerization capacity of RCI14A (Abarca et al., 1999). This effect involves the C-terminal end of RCI14A and might also modulate the interaction of this 14-3-3 protein with its binding partners. The cationic effect of calcium seems to be specific as Mg2+ has no effect on dimerization.
A requirement for millimolar concentrations of divalent cations like calcium, magnesium and manganese has also been demonstrated for the formation of inactive 14-3-3:NR complexes at pH 7.5 (Athwal et al., 1998a). However, this requirement is strictly pH-dependent and is far less pronounced at pH 6.5. Binding of cations and lowering the pH cause conformational changes of 14-3-3 proteins, leading to an increase in surface hydrophobicity. These conformational changes might be necessary to ‘prime’ 14-3-3 proteins prior to binding of target proteins as suggested by Athwal et al. (1998a). Physiologically, magnesium seems to be the only divalent cation present in sufficient concentrations to cause such an effect. However, a recent publication introduced the possibility that polyamines may act as in vivo effectors of 14-3-3 activity (Athwal and Huber, 2002). The authors showed that the effect observed with millimolar concentrations of divalent cations at pH 7.5 could be achieved with micromolar concentrations of polyamines. Thus a product of metabolism itself might be required to switch 14-3-3 proteins into a state in which binding to target proteins becomes possible.
14-3-3 structure may also affect its own phosphorylation. As shown by Megidish et al. (1998), a sphingosine- or N,N'-dimethylsphingosine-activated protein kinase (SDKs) specifically phosphorylates certain endogenous mouse 14-3-3 isoforms. The phosphorylation site is located on the dimer interface of 14-3-3 proteins, and it is likely that phosphorylation alters dimerization or induces conformational changes that alter the association of 14-3-3 proteins with other kinases.
Phosphorylation of 14-3-3 proteins may also prevent association with certain target proteins. In mammals, a casein kinase I 
was able to phosphorylate 14-3-3 proteins (Dubois et al., 1997). The mammalian 14-3-3 isoforms 
and 
possess a phosphorylatable serine residue and it has been shown previously that only the unphosphorylated associates with the regulatory domain of c-Raf (Rommel et al., 1996).
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Regulation and localization of 14-3-3 expression |
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TopAbstractIntroduction14-3-3 proteins in plants14-3-3 proteins regulate plant...14-3-3 proteins regulate key...Interaction of 14-3-3 proteins...14-3-3 proteins interact with...14-3-3 proteins bind to...Structure, function, modulationRegulation and localization of...Conclusion and perspectivesReferences |
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It is known that 14-3-3 proteins can modulate responses to environmental changes via interactions with key enzymes, but the expression of 14-3-3s can also be affected by different environmental challenges. Expression of a rice 14-3-3 cDNA is regulated by external stresses such as salt and low temperatures (Kidou et al., 1993). Similarly, the expression of two Arabidopsis 14-3-3 cDNAs is induced by low temperatures (Jarillo et al., 1994).
Numerous investigations of 14-3-3 expression patterns in animal systems performed in the early 90s showed organ- and tissue-specific expression of diverse 14-3-3 genes, and developmental expression was seen in rat brain (Watanabe et al., 1991, 1993, 1994). Later, Daugherty et al. (1996) showed that the Arabidopsis gene coding for 14-3-3
also exhibits cell- and tissue-specific expression in roots of seedlings and mature plants.
Recently, Rosenquist et al. (2001) identified two new 14-3-3 genes showing tissue-specific expression in Arabidopsis. Cell- or tissue-specific expression of 14-3-3 genes can also be found in tomato. Expression analysis of ten tomato 14-3-3 isoforms revealed that specific subsets of the genes were induced in leaves during a gene-for-gene resistance response. Different developmental patterns of 14-3-3 expression in response to fusicoccin or elicitor treatments were also shown (Roberts and Bowles, 1999). In potato, the expression of five 14-3-3s in leaves clearly depends on the developmental stage (Wilczynski et al., 1998).
However, changes in gene expression do not necessarily reflect the quantity of 14-3-3s. Despite the clear induction of three barley 14-3-3 mRNAs upon imbibition, protein levels remain constant during germination (Testerink et al., 1999). More significance may lie in the finding of subcellular, germination-dependent differences in post-translational protein modifications between the three barley 14-3-3 isoforms (van Zeijl et al., 2000).
In addition to regulatory factors, subcellular localization of 14-3-3 isoforms may contribute to their specificity. Although 14-3-3 proteins were thought to be solely soluble cytosolic proteins, Martin et al. (1994) demonstrated that some mammalian isoforms were tightly associated with membranes. In plants, 14-3-3 isoforms have been identified in the cytosol, the nucleus (Bihn et al., 1997), in the mitochondrial matrix (Bunney et al., 2001) and in the chloroplast stroma and the stromal side of thylakoid membranes (Sehnke et al., 2000). Sehnke et al. (2000) also showed that localization of 14-3-3 proteins can be isoform-exclusive, as only the Arabidopsis 14-3-3 isoforms 
, , µ, and 
are present in the chloroplast stromal extract whereas the cytosolic isoform 
is excluded from chloroplasts.
Despite clear spatial and temporal regulation of 14-3-3 gene expression and organelle specific localization of 14-3-3 proteins, the question whether many 14-3-3 isoforms are necessary or redundant remains unclear. As outlined above, 14-3-3 proteins present a high degree of structural conservation in the binding groove. This may allow all isoforms to bind to the same target proteins. However, the less conserved C-terminal region may confer some degree of isoform specificity during binding (Finnie et al., 1999). It has also been suggested that the presence of different 14-3-3 isoforms allows the formation of specific heterodimers with unique recognition of ligands (Yaffe, 2002). Another hypothesis is that a high number of isoforms ensures that 14-3-3 proteins are present and active in all cell compartments (DeLille et al., 2001), and, of course, it can not be ruled out that each isoform displays a specific activity in vivo.
Although the data published on 14-3-3 specificity is growing steadily, many results still appear contradictory. For example, there is evidence that an Arabidopsis thaliana isoform can substitute for the functions of yeast and mammalian isoforms (Lu et al., 1994; van Heusden et al., 1995). In mammals, the 14-3-3 binding peptide R18 which occupies the general binding groove of 14-3-3 can bind different mammalian 14-3-3 isoforms with similar affinities (Wang et al., 1999). In plants, Holtman et al. (2000) have shown that three barley 14-3-3 proteins interact with similar properties with a 13-lipoxygenase in surface plasmon resonance experiments, suggesting that different isoforms do not display binding specificity.
However, there is an increasing body of evidence for 14-3-3 binding specificity. Firstly, both animals and plants have two groups of 14-3-3 proteins, the group and the non- group. Ferl et al. (1994) suggested that these two may have different functions in mammals. Evidence for 14-3-3 isoform specificity has been reported in animal cells. For example, Vincenz and Dixit (1996) showed that both the zinc finger protein A20 and c-Raf bind preferentially the 
-isoform, followed by the -isoform whilst the ß-, - and 
-isoforms bind less well. In plants, variation in binding specificity of 14-3-3 proteins to NR has been shown by Bachmann et al. (1996a) and Kanamaru et al. (1999). The binding of only five of the Arabidopsis 14-3-3 isoforms to GST-hTFIIB beads also shows affinity differences (Pan et al., 1999). In this case, no dimer formation was required and no known motif containing phosphoserine was identified. Even the plasma membrane H+-ATPase of Vicia faba has been shown to have a higher affinity for vf14-3-3a than for vf14-3-3b (Emi et al., 2001). Surface plasmon resonance experiments demonstrated strong variations in relative binding affinity between nine of the Arabidopsis 14-3-3 isoforms and a peptide representing the last 15 amino acids of the plasma membrane H+-ATPase AHA2 (Rosenquist et al., 2000).
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Conclusion and perspectives |
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TopAbstractIntroduction14-3-3 proteins in plants14-3-3 proteins regulate plant...14-3-3 proteins regulate key...Interaction of 14-3-3 proteins...14-3-3 proteins interact with...14-3-3 proteins bind to...Structure, function, modulationRegulation and localization of...Conclusion and perspectivesReferences |
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It is believed that the evidence summarized in this review clearly demonstrates the importance of 14-3-3 proteins in the regulation of primary plant metabolism. The possible co-ordination of primary carbon and nitrogen metabolism via 14-3-3 proteins presents an interesting perspective. Depending on the developmental and environmental requirements, 14-3-3 activity could direct carbon either into sucrose and storage carbohydrate synthesis or, via inactivation of carbon metabolism and activation of nitrogen assimilation, divert carbon skeletons into the synthesis of amino acids.
Despite many investigations into the role of individual 14-3-3 proteins and their interaction with target proteins, the means of 14-3-3 protein specificity remains largely unknown. First insights into this question have been gained by analysing gene-specific expression of 14-3-3 genes. However, these analyses require clarification by determining the fate of 14-3-3 proteins. It is believed that the great number of 14-3-3 proteins, rather than being a nuisance to researchers due to their apparent redundancy, offer the chance of studying fine regulatory mechanisms of metabolic pathways. Plants could use the various possible combinations of 14-3-3 homo- and heterodimers for fine-tuning of metabolism in response to changes in the environment or internal demands.
As exemplified in this review, many details are known about 14-3-3 proteins. Unfortunately, these facts are spread across different phyta and are made using different experimental systems. What is needed is a systematic approach to investigate the roles of each isoform in a single system. Completion of the Arabidopsis genome sequencing programme and the opportunities offered by functional genomics, proteomics and metabolomics facilities make Arabidopsis an excellent plant model for such an approach. A reverse genetic approach is currently being adopted to identify mutants in 14-3-3 genes. These mutants will be systematically compared to wild-type plants with the ultimate aim being the resolution of 14-3-3 function and specificity in the regulation of plant metabolism.
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Acknowledgements |
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We gratefully acknowledge financial support for our work by the BBSRC and the Royal Society.
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References |
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