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J. Biol. Chem., Vol. 277, Issue 10, 7629-7632, March 8, 2002

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MINIREVIEW
Synaptotagmins: Why So Many?^*

Thomas C. Südhof

From the Center for Basic Neuroscience, Department of Molecular Genetics, and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9111

	INTRODUCTION

TOP INTRODUCTION Structures of Synaptotagmins Genes and Alternative Splicing... Synaptotagmin C2-Domains Functional Properties of... A Working Model for... REFERENCES

Synaptotagmins constitute a family of membrane-trafficking proteins that are characterized by an N-terminal TMR,¹ a variable linker, and two C-terminal C₂-domains (1). Synaptotagmin 1 (Syt 1) was identified as p65 in a monoclonal antibody screen for synaptic proteins (2) and proposed as a potential Ca²⁺ sensor for regulated exocytosis when its cloning revealed the presence of two C₂-domains (3). Twelve additional synaptotagmins were subsequently discovered (Fig. 1 and Table I; Refs. 4-14). Extensive work showed that Syts 1 and 2 likely function as Ca²⁺ sensors in synaptic vesicle exocytosis (15-19). Much less is known about the other synaptotagmins, although many of them are abundantly co-expressed with Syts 1 and 2 in brain and are evolutionarily conserved. The most abundant of these "other" synaptotagmins, Syts 3 and 7, are localized on the plasma membrane opposite to synaptic vesicles and exhibit distinct Ca²⁺ affinities, suggesting that plasma membrane and vesicular synaptotagmins may function as complementary Ca²⁺ sensors in exocytosis with a hierarchy of Ca²⁺ affinities (20-22). In the present short review, I shall discuss the synaptotagmin family as a whole and evaluate possible biological reasons for the co-expression of multiple isoforms.

	Structures of Synaptotagmins

TOP INTRODUCTION Structures of Synaptotagmins Genes and Alternative Splicing... Synaptotagmin C2-Domains Functional Properties of... A Working Model for... REFERENCES

We classify as a synaptotagmin any protein that has an N-terminal TMR, a central linker, and two C-terminal C₂-domains (Fig. 1). Based on their sequences and properties, the 13 vertebrate synaptotagmins can be grouped into 6 classes (Table I).

View larger version (28K): [in this window] [in a new window]   Fig. 1.   Domain structures of synaptotagmins 1-13: relation of protein domains to the intron/exon organization of the human genes. Each diagram shows a single or several closely related synaptotagmins as identified on the left. Arrows indicate positions of introns in the corresponding human genes as identified in the human genome sequence.2 The numbers next to the arrows describe the position in the codon at which the coding sequence is interrupted by the intron (0, at the codon junction; 1 and 2, after the first and second codon position, respectively). The N-terminal TMR is marked with a T, and the C2A- and C2B-domains are labeled.

Fig. 1 displays the domain structures of synaptotagmins and the positions of the introns in the corresponding human genes.² The N-terminal sequences preceding the TMRs are usually short (4-62 residues) and exhibit significant sequence similarity only within a given class. Syts 1 and 2 are the only synaptotagmins with an N-glycosylated N terminus (4, 23), and Syts 3, 5, 6, and 10 are the only synaptotagmins with disulfide-bonded cysteines at the N terminus (24). The TMRs of synaptotagmins also lack significant sequence similarity. In all synapotagmins except for Syt 13, an intron is placed just N-terminal to the TMR,² and all synaptotagmins except for Syt 12 contain cysteine residues at the cytoplasmic boundary of the TMR. At least in Syts 1 and 7, some of these cysteines are palmitoylated (25-27). Synaptotagmins form constitutive dimers via their TMRs in a reaction that may require palmitoylation (23, 27). One possible reason for the constitutive dimerization of synaptotagmins is to protect them from cleavage by -secretase since -secretase promiscuously cleaves monomeric but not dimeric membrane proteins containing a short extracellular stub (28). The size of the linker between the TMR and the C₂-domains varies from 43 residues for Syt 8 to 417 residues for the longest splice variant of Syt 7 (Fig. 1). At least in Syt 1, the linker is phosphorylated by multiple protein kinases (29, 30).

The C-terminal C₂-domains of synaptotagmins, referred to as the C₂A- and C₂B-domains, account for the majority of their sequences and represent their only homologous sequences (Fig. 1). C₂-domains are widespread modules of 130-140 residues that were initially defined as the second constant sequence (hence "C₂") in protein kinase C isoforms (31) and were first shown in Syt 1 to constitute Ca²⁺-binding modules (32-34). Atomic structures revealed that the synaptotagmin C₂A- and C₂B-domains are similarly composed of a -sandwich containing eight -strands, with flexible loops emerging from the top and the bottom (35, 36). C₂A-domains generally bind three Ca²⁺ ions, whereas C₂B-domains bind only two Ca²⁺ ions (Fig. 3) (Refs. 36-38; but see below for exceptions). All C₂B-domains contain a bottom -helix between the 7th and 8th -strands that is absent from C₂A-domains (35-38). The fact that the differences between the C₂A- and C₂B-domains are conserved indicates a common ancestry and suggests that the C₂-domains are functionally specialized in all synaptotagmins (1).

In addition to synaptotagmins, proteins such as rabphilin and Doc2s contain similar C₂A- and C₂B-domains but are not classified as synaptotagmins because they lack TMRs (reviewed in Ref. 1). Furthermore, two other protein families (called Vp115 and ferlins) contain multiple C₂-domains and a TMR similar to synaptotagmins but differ from synaptotagmins in that they have more than two C₂-domains (39-44).

	Genes and Alternative Splicing of Synaptotagmins

TOP INTRODUCTION Structures of Synaptotagmins Genes and Alternative Splicing... Synaptotagmin C2-Domains Functional Properties of... A Working Model for... REFERENCES

Analysis of the human genome revealed that synaptotagmin genes vary from <10 kilobases (Syts 8 and 9) to >60 kilobases (Syt 1), and are not physically linked.² The exon/intron structures of synaptotagmin genes are nearly identical for synaptotagmins within a class but differ dramatically between classes. Some synaptotagmin genes are relatively simple (e.g. the Syt 4 and 11 genes contain only four exons), whereas others are complex (the Syt 7 gene with 14 exons; Fig. 1). Only a single exon (at the beginning of the C₂B-domain) is shared among all synaptotagmins, making this exon a signature of synaptotagmin genes.

Alternative splicing of the linker sequence between the TMR and the C₂-domains of synaptotagmins and of the TMR itself have been reported. Alternative splicing of a short sequence in the linker of Syt 1 (3) probably represents a sliding exon/intron junction. Strikingly, the Syt 7 linker region is subject to extensive alternative splicing with dramatic changes in protein structure (21). Five exons are variably included or excluded in the mRNA (Fig. 1), resulting in a 10-fold expansion or contraction of the linker. One of the five alternatively spliced exons features an evolutionarily conserved stop codon; insertion of this exon creates a truncated Syt 7 protein (21). The alternative splicing of Syt 7 is developmentally and regionally regulated, suggesting that it regulates the coupling of the C₂-domains to the TMR (21).

PCR experiments suggested that for many synaptotagmins, variants lacking TMRs are produced by "exon skipping" (45, 46). However, the gene structures of these synaptotagmins show that exon skipping would create out-of-frame junctions between the N- and C-terminal exons (Fig. 1). This result together with the fact that no soluble synaptotagmins were observed make the alternative splicing of synaptotagmin TMRs doubtful.

	Synaptotagmin C2-Domains

TOP INTRODUCTION Structures of Synaptotagmins Genes and Alternative Splicing... Synaptotagmin C2-Domains Functional Properties of... A Working Model for... REFERENCES

The synaptotagmin C₂-domains are functionally polarized in that Ca²⁺ exclusively binds to the top loops but not the bottom loops (36-38, 47, 48). Diverse activities have been reported for synaptotagmin C₂-domains. In assessing potential interactions of C₂-domains, structural implications are unfortunately often ignored in favor of "functional" interpretations. For example, experiments with peptide injections into nerve terminals (49) led to the conclusion that the characteristic C-terminal WHXL sequence of the Syt 1 C₂B-domain functions in synaptic vesicle docking. In the folded C₂B-domain, however, the WHXL sequence forms a stably bonded -strand (36) that is unlikely to unfold under physiological conditions. Another example is the AD3 mutant in Drosophila (18, 19). The AD3 mutation changes a conserved -strand of the C₂B-domain and likely interferes with its folding. Claims about testing specific binding activities of the C₂B-domain with the AD3 mutant domain (50, 51) are thus difficult to interpret. Similar reservations apply to other studies of synaptotagmins that involve sequences with conserved secondary structures.

Ca²⁺ and Phospholipid Binding-- C₂-domains bind Ca²⁺ exclusively via their top loops (33, 47). Fig. 2 shows a model of the Ca²⁺-binding sites of the Syt 1 C₂-domains (36, 38). The Ca²⁺-binding sites of C₂-domains are unusual because Ca²⁺ ions are coordinated by residues that are widely separated in the primary sequence and because the coordination spheres for the Ca²⁺ ions are incomplete (16, 47). The intrinsic Ca²⁺ affinities of the C₂-domains are low (K_d >1 mM and >0.3 mM for the Syt 1 C₂A- and C₂B-domains, respectively (16, 36)). Ca²⁺ binding to C₂-domains (except for the unusual piccolo/aczonin C₂-domain (52)) does not cause significant conformational changes (36-38), suggesting that C₂-domains function as electrostatic switches whereby Ca²⁺ binding triggers interactions by altering their surface charge (48).

View larger version (23K): [in this window] [in a new window]   Fig. 2.   Structure of the Ca2+-binding sites of the C2A- and C2B-domains of synaptotagmins. The diagram shows a generic model for synaptotagmin Ca2+-binding sites that is based on the structure of the C2A- and C2B-domains of Syt 1 (36, 38). The Ca2+-binding sites at the top of the synaptotagmin C2-domains are formed by loops 1 (right blue line) and 3 (left blue line). The C2A-domain ligates three Ca2+ ions via five aspartate and one serine residue, whereas the C2B-domain lacks the binding site for Ca3 and ligates only two Ca2+ ions. The model is proposed for Syts 1-7 and 9-11, whereas Syts 8, 12, and 13 lack almost all of the Ca2+-binding residues. In Syts 4 and 11, one of five Ca2+-binding aspartates in the C2A-domain is substituted for a serine residue, suggesting that this C2A-domain may only bind one or two Ca2+ ions (11).

The C₂-domains of Syt 1 bind phospholipids as a function of Ca²⁺ with apparent Ca²⁺ affinities (1-20 µM Ca²⁺) that are 100-10,000-fold the intrinsic Ca²⁺ affinities (16, 36). This dramatic increase probably occurs because the docked phospholipids on top of the C₂-domains provide additional coordination sites for the incomplete Ca²⁺-binding spheres (16, 53). It is likely that phospholipid binding by most synaptotagmins is functionally important but not all synaptotagmins bind Ca²⁺ and phospholipids. For example, Syts 4 and 11 have an evolutionarily conserved substitution in the Ca²⁺-binding site of the C₂A-domain (Fig. 2; Ref. 11) that prevents binding of a full complement of Ca²⁺ ions. In Syts 8, 12, and 13, the top loops of the C₂A- and the C₂B-domains lack almost all of the aspartate and glutamate residues involved in Ca²⁺ binding.

Ca²⁺-dependent Self-association-- The recombinant C₂B-domains, but not C₂A-domains, of most synaptotagmins pull down native Syt 1 and Syt 2 from brain in a Ca²⁺-dependent manner (54-57). This activity suggests a potential mechanism by which C₂B-domains could mediate Ca²⁺-dependent polymerization of synaptotagmins during exocytosis. Some studies detected Ca²⁺-dependent multimerization of recombinant C₂-domains (56-58), whereas others did not (54, 55). Structural characterization of the Syt 1 C₂B-domain revealed that the electrophoretically pure C₂B-domain contains stoichiometric amounts of bacterial contaminants (probably polynucleotides and lipids) that are tightly attached to a polybasic sequence (LKKKKT) on the C₂B-domain, cause domain aggregation, and are only removed by harsh washes (59). C₂B-domain that was cleared of bacterial contaminants exhibited competent Ca²⁺ binding but no self-association even at millimolar Ca²⁺ (59), but native Syt 1 formed Ca²⁺-dependent high molecular weight complexes, indicating that Ca²⁺-dependent self-association (54, 55) may prove relevant but utilize a more complex mechanism.

Interactions with SNAREs-- Most synaptotagmins bind to syntaxin 1 in a Ca²⁺-dependent manner (7), suggesting an intersection of the mechanism of fusion (via the SNARE protein syntaxin) with the Ca²⁺-dependent regulation of fusion (via Syt 1) (reviewed in Ref. 60). However, the precise nature of this interaction is unclear. Binding of Syt 1 to syntaxin, SNAP-25 (another SNARE protein), and assembled SNARE complexes has been reported (7, 51, 61-63). Synaptotagmin-binding sites on syntaxin have been localized on the N-terminal Habc domain (63) and the C-terminal SNARE motif (61).

Binding to Endocytosis Proteins-- All synaptotagmins tested (Syts 1-7) interact with AP-2 with high affinity (7, 64), and binding is enhanced by hydrophobic peptides (65). Transfection of truncated synaptotagmins inhibits clathrin coat assembly and endocytosis in fibroblasts, suggesting that synaptotagmins have a physiological role in endocytosis (26). In Drosophila, mutations in the stoned gene cause a defect in synaptic vesicle endocytosis and also a mislocalization and destabilization of Syt 1 (66, 67). Mammalian stoned proteins may also interact with Syt 1, suggesting that this could be a general mechanism in synaptic vesicle endocytosis (68, 69).

Binding of Inositol Phosphates-- The C₂B-domains of most synaptotagmins bind to inositol polyphosphates via the short polybasic sequence that contains bacterial contaminants in recombinant C₂B-domains (70). Binding does not require the folded C₂B-domain but is obtained with the isolated polybasic sequence. Inhibition of neurotransmitter release by inositol polyphosphates suggests that inositol phosphate binding to synaptotagmin physiologically regulates release (71). However, hundreds of synaptic proteins may bind to inositol phosphates, and the specific role of synaptotagmin is unknown.

	Functional Properties of Individual Synaptotagmins

TOP INTRODUCTION Structures of Synaptotagmins Genes and Alternative Splicing... Synaptotagmin C2-Domains Functional Properties of... A Working Model for... REFERENCES

Class 1: Syts 1 and 2 as Vesicular Ca²⁺ Sensors-- Syts 1 and 2 are localized to synaptic vesicles and secretory granules (2-4, 22), are closely related, and are differentially expressed in a largely non-overlapping pattern (4, 72, 73). Syts 1 and 2 probably function as an essential Ca²⁺ sensor in fast synaptic vesicle exocytosis (15) as shown by a point mutation that was introduced into the endogenous mouse genome (16). This mutation caused an approximately 2-fold decrease in the apparent Ca²⁺ affinity of Syt 1 and a similar decrease in the Ca²⁺ sensitivity of synaptic vesicle exocytosis, indicating that Ca²⁺ binding to Syt 1 is an essential step in triggering exocytosis. However, Syts 1 and 2 are not the only Ca²⁺ sensor because some Ca²⁺-dependent exocytosis remains in their absence (15, 17, 18). In addition to exocytosis, Syt 1 may also function in endocytosis as discussed above.

Class 2: Syt 7 as an Active Zone Ca²⁺ Sensor-- Syt 7, together with Syt 3, is the most abundant synaptotagmin after Syts 1 and 2. Syt 7 is expressed predominantly in brain (7, 21, 72, 73) where it is primarily present on plasma membranes (20, 21). Confusingly, in cultured cells Syt 7 has been reported in lysosomes (76). However, the antibody used in that study did not detect Syt 7 in brain, making the localization of Syt 7 in non-neuronal cells uncertain. The C₂-domains of Syt 7 have a 10-20-fold higher Ca²⁺ affinity than those of Syts 1 and 2 (22) and self-associate as a function of Ca²⁺ (77). In permeabilized PC12 cells, recombinant C₂A- and C₂B-domains of Syt 7 severely inhibit exocytosis (21). C₂-domains of Syt 1, by contrast, had no effect consistent with the fact that Syt 1 is not essential for Ca²⁺-triggered exocytosis in PC12 cells as opposed to synapses (78). Inhibition by recombinant Syt 7 C₂-domains required intact Ca²⁺-binding sites, suggesting that plasma membrane Syt 7 in PC12 cells functions as a Ca²⁺ sensor for exocytosis.

Class 3: Syts 3, 5, 6, and 10 as Plasma Membrane Ca²⁺ Sensors-- Similar to Syt 7, Syts 3 and 6 are localized to plasma membranes, have a 10-fold higher Ca²⁺ affinity than Syts 1 and 2, and probably function in Ca²⁺-triggered PC12 exocytosis (22, 79). Syt 10 was identified as a seizure-inducible mRNA and may have a function related to neuronal excitability (10).

Class 4: Syts 4 and 11-- Syts 4 and 11 are encoded by the simplest genes among synaptotagmins (Fig. 1). Their characteristic feature is a conserved substitution of an aspartate for a serine residue in the C₂A-domain (Fig. 2) that changes the Ca²⁺-binding properties of the C₂A-domain (11). Syt 4 is expressed at highest levels early during postnatal development (79) but is strongly induced by seizures in adult brain (80) and by increases in cAMP or Ca²⁺ in PC12 cells (81). Immunocytochemistry of brain sections, cultured neurons, and transfected cells localized Syt 4 in the Golgi apparatus (79, 82). In contrast, the Drosophila Syt 4 homolog was observed in synaptic vesicles (83).

The function of Syts 4 and 11 is also uncertain. Microinjection of Syt 4 fragments into PC12 cells (84) and overexpression of Drosophila Syt 4 inhibited exocytosis (83). A knockout of Syt 4 in mice uncovered a subtle but interesting phenotype that is consistent with a modulatory role at the synapse (85). Nothing is known about the expression and localization of Syt 11, but the similarity between Syts 4 and 11 suggests that they are redundant.

Class 5: Syt 9-- Syt 9 (also called Syt 5 (7-9)) is synthesized at low abundance in brain and non-neuronal cells (8, 9) and localized to synaptic vesicles (8).

Class 6: Atypical Syts 8, 12, and 13 That Lack Consensus Ca²⁺-binding Sites-- Very little is also known about these synaptotagmins. Syt 12 was initially discovered as a thyroid hormone-regulated transcript (12), indicating a specialized function in brain that could be related to thyroid-dependent developmental changes.

	A Working Model for Synaptotagmin Function

TOP INTRODUCTION Structures of Synaptotagmins Genes and Alternative Splicing... Synaptotagmin C2-Domains Functional Properties of... A Working Model for... REFERENCES

Vertebrates express at least 13 synaptotagmins that are synthesized exclusively or predominantly in neurons and neuroendocrine cells. By virtue of their C₂-domains, most synaptotagmins are membrane-bound Ca²⁺-signaling machines. The presence of distinct synaptotagmins on the membranes of synaptic vesicles and active zones, the membranes that have to fuse during neurotransmitter release, suggests a potential explanation for the existence of multiple synaptotagmins. The model in Fig. 3 proposes that at least Syts 1, 2, 3, 6, and 7 perform complementary functions in Ca²⁺-triggered exocytosis whereby Ca²⁺ binding to each class of synaptotagmins contributes differently to triggering exocytosis. As Ca²⁺ sensors, all synaptotagmins share the same Ca²⁺ cooperativity and Ca²⁺-dependent phospholipid binding but have distinct Ca²⁺ binding properties. Vesicular synaptotagmins have a lower Ca²⁺ affinity and are more important in fast synaptic exocytosis than in endocrine exocytosis, the bulk of which is much slower (15, 16, 75). Plasma membrane synaptotagmins, in contrast, have a higher Ca²⁺ affinity and may be more important for endocrine exocytosis (21, 22). With these distinct properties, the combination and relative abundance of various synaptotagmins could contribute to shaping the characteristic Ca²⁺ responses of synapses.

View larger version (22K): [in this window] [in a new window]   Fig. 3.   Geometry of synaptotagmins during exocytosis. One class of synaptotagmins (Syts 1 and 2 and possibly Syts 4, 9, and 11) are located on synaptic vesicles or secretory granules, whereas a second set (Syts 3, 6, and 7 and possibly others) are targeted to the plasma membrane, creating a symmetrical arrangement of opposing Ca2+-sensors. All synaptotagmins are probably dimers via interactions in the TMR and/or disulfide bonds between the extracytoplasmic N-terminal regions (for Syts 3, 5, 6, and 10). In addition to Ca2+-dependent interactions of the C2-domains of synaptotagmins with phospholipids, at least some synaptotagmins also bind to themselves and each other via Ca2+-dependent interactions that may be mediated by the C2B-domains (modified from Ref. 22).

Although the model proposed for synaptotagmin function (Fig. 3) is attractive because it provides an explanation for the unprecedented Ca²⁺ control of neurotransmitter release, it is as yet only a working hypothesis. Questions abound. For example, is Ca²⁺ binding to a single type of synaptotagmin sufficient to trigger exocytosis, what is the functional relation between different C₂-domains of synaptotagmins, and how do synaptotagmins precisely work in exocytosis? If synaptotagmins are Ca²⁺-signaling machines, why do some synaptotagmins lack Ca²⁺-binding sites? Another set of questions regards the potential role of synaptotagmins in endocytosis and the possibility that at least some of them may be expressed outside of neurons and endocrine cells. Addressing these questions will be essential for further progress.

	ACKNOWLEDGEMENTS

I thank Drs. J. Rizo, R. Jahn, and E. Kavalali for innumerable discussions.

	FOOTNOTES

^* This minireview will be reprinted in the 2002 Minireview Compendium, which will be available in December, 2002.

To whom correspondence should be addressed: Center for Basic Neuroscience, Dept. of Molecular Genetics, Howard Hughes Medical Inst., University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd. NA4.118, Dallas, TX 75390-9111. Tel.: 214-648-1976; Fax: 214-648-1879; E-mail: Thomas.Sudhof@UTSouthwestern.edu.

Published, JBC Papers in Press, December 5, 2001, DOI 10.1074/jbc.R100052200

² T. C. Südhof, unpublished observation.

	ABBREVIATIONS

The abbreviations used are: TMR, transmembrane region; Syt 1-Syt 13, synaptotagmins 1-13; SNARE, soluble N-ethylmaleimide-sensitive factor attachment protein receptor; AP-2, adaptor protein 2.

	REFERENCES

TOP INTRODUCTION Structures of Synaptotagmins Genes and Alternative Splicing... Synaptotagmin C2-Domains Functional Properties of... A Working Model for... REFERENCES

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