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First published online June 28, 2004
doi: 10.1242/10.1242/jcs.01290

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The syndapin protein family: linking membrane trafficking with the cytoskeleton

Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology, Brenneckestr. 6, 39118 Magdeburg, Germany

View larger version (43K): [in a new window]   Fig. 1. Interactions of the syndapin protein family. Depicted are all syndapin interaction partners described thus far, irrespective of species, syndapin isoform or splice variant. Note that the depicted antiparallel dimers are merely a hypothetical model for syndapin oligomerization, which is not yet supported by a crystal structure. The thickness of the arrows indicates whether the interactions are based on in vitro data, supported by in vivo interaction studies or confirmed by functional analyses of the respective cellular functions and corresponding rescue experiments.

View larger version (61K): [in a new window]   Fig. 2. Interconnection of dynamin-mediated vesicle fission with Arp2/3-complex-dependent F-actin nucleation triggered by N-WASP and syndapins. (A) Early in vesicle formation, the membrane is deeply invaginated and dynamin starts to concentrate at the vesicle neck, which is still wide. Syndapin oligomers associated with dynamin may help recruit and activate the Arp2/3 complex activator N-WASP (1). In this way, actin nucleation by the Arp2/3 complex can be linked to dynamin-mediated fission control (2). Actin filaments can be generated de novo (2) and as new branches from already existing actin fibres that may be part of the cortical cytoskeleton (3). It remains to be investigated whether syndapin-dynamin complexes form first in the cytosol (4), after dynamin has been recruited to the plasma membrane (5) or both. (B) Late in vesicle formation, the vesicle neck is constricted and the vesicle is subsequently pinched off and detached from the plasma membrane. Dynamin oligomers surrounding the neck could be a spatial and temporal cue for Arp2/3-complex-mediated F-actin nucleation. Syndapins and N-WASP serve as connecting elements that ensure that actin polymerization is restricted to the neck region. Such a restriction of actin build-up and a polarization of actin fibres in a manner that orientates the fast-growing plus ends towards the forming/moving vesicle provides force and ensures the directionality of vesicle movement away from the donor membrane. Growing plus ends of actin filaments are marked by ATP-loaded actin monomers, which are depicted in darker blue. PIP2, phosphatidylinositol (4,5)-bisphosphate.

View larger version (49K): [in a new window]   Fig. 3. Unrooted phylogenetic tree of syndapins produced from a ClustalW alignment of 36 syndapin sequences by the TreeTop phylogenetic tree reconstruction software (http://www.genebee.msu.su/services/phtree_reduced.html). Published syndapin sequences or consensus sequences from as many expressed sequence tag (EST) clones as could be identified in the NCBI databases were used. More than 150 syndapin-related DNA sequences were analysed. Few of those have been described at the protein level (only some vertebrate syndapins and the antigens EG13 and EM13 from band worms). The tree is based on an alignment of the first 120 residues of rat syndapin I with corresponding regions of all syndapin proteins and predicted proteins from DNA sequences in the databases. Parallel phylogenetic tree constructions were performed with the first 210 residues (32 sequences) and 305 residues (28 sequences), respectively. These gave very similar results. The same is true for alignments with blunted N-termini. Note that the confidence levels of the branch points that have scores of 63-73% in the above analysis are enhanced to 82-99% in analyses using longer sequences. Protostomia: parasitic band worms, Echinococcus granulosus (EG13, GI:158845) and Echinococcus multilocularis (EM13, GI:158849); roundworms, Caenorhabditis elegans (GI:17567724, gene XI608); identified but not included (due to degenerated DNA sequence or lack of N-terminus) were, Caenorhabditis briggsae (genome contig FPC4044) and a sequence from the most primitive plathelminthes, the turbellaria (Schmidtea mediterranea; GI:21308965). Insects: Drosophila melanogaster, GI:28571784; Anopheles gambiae, overlapping ESTs (GI:31224233 and GI:31224240) and new entry for assembled gene GI:21300122; Bombyx mori (domestic silk worm), GI:37662803, not included. Deuterostomia: there are extremely few sequence data for all organisms originating from the basis of this line (hemichordata and echinodermata, such as starfish) and for the most primitive chordata (the tunicata, the copelata and the acrania). Fish and higher vertebrates, however, were analysed. Fish: Fugu rubripes (fugu fish): syndapin I (SINFRUP00000064571 and FuguGenscan_5227), syndapin II (SINFRUP00000062952 and FuguGenscan_1173), syndapin III (SINFRUP00000059173), syndapin IV (FuguGenscan_14767) and syndapin V (FuguGenscan_30629); Danio rerio (zebra fish), syndapin I (GI:156355 and GI:17239474), syndapin II (GI:31063171, GI:39660160, GI:6949740 and GI:16098827), syndapin III (GI:28279267), syndapin IV (GI:38647966 and GI:13104055) and syndapin V (GI:38554082, GI:38540910 and GI:23193087); Ictalurus punctatus (channel cat fish), syndapin II (GI:40583787) and III (GI:40581408, GI:18646500 and GI:33607133); Cyprinus carpio (carp), syndapin V (GI:37560134, GI:37557575 and GI:27491180) and Oncorhynchus mykiss (rainbow trout), syndapin V (GI:39964270, GI:29590006, GI:24697026 and GI:24681637). Syndapins from other fish, such as Oryzias latipes (Japanese rice fish) were identified (GI:17373342 and 17368378) but not included in the above analysis. Birds and frogs: Gallus gallus (chicken), syndapin I (GI:25737679 and GI:15085432, not included), syndapin II/FAP52 (GI:2217963); syndapin III (GI:25904662 and GI:25953223) and Xenopus laevis (African clawed frog), syndapin I (GI:31090847), X-PACSIN2/syndapin II (GI:11558503) and syndapin III, GI:27469860). Mammalia: Sus scrofa (pig), syndapin II (GI:37854627), syndapin III (GI:40437003, GI:11075716 and GI:40437003), Bos taurus (cow), syndapin II (GI:9747526, GI:24332175 and GI:9601216), Canis familiaris (dog), syndapin II (GI:23699945 and GI:23699935, not included), syndapin III (GI:34413292 and 23707795, not included). The sequences of the three isoforms from rat, mouse and human included in the phylogenetic analyses have mostly been published, and these have in part been studied at the protein level: Rattus norvegicus (rat), syndapin I (GI:4324451), syndapin II consensus sequence of syndapin IIaa, IIbb, IIab and IIba (GI:6651162, GI:6651168, GI:6651164, GI:6651166), syndapin III (GI:27702145 and M.M.K. and B.Q., unpublished, respectively); Mus musculus (mouse), syndapin isoform I called h74 or PACSIN (GI:2632077), PACSIN2 (GI:19483912) and PACSIN3 (GI:13539689); Homo sapiens (man), PACSIN1 (GI:25955520), a consensus of the long PACSIN2 version and a shorter syndapin II splice variant (GI:6005825 and GI:12053194) and PACSIN3 (GI:11127645). Note that the database entries for so-called syndapin-II-related proteins in Dictyostelium discoideum rather represent a homologue of PSTPIP (GI:28828180) and a formin-binding protein 17 homologue (GI:21240669), respectively.

View larger version (68K): [in a new window]   Fig. 4. Immunofluorescence microscopy images of syndapin isoforms I, II and III in different cell types. (A) Rat hippocampal neurons in culture immunostained for syndapin I (green) and for the synaptic vesicle marker synaptophysin (red); merged confocal image, colocalization appears yellow. Reproduced with permission from The American Society for Cell Biology (Qualmann et al., 1999). (B,C) Isolated rabbit lacrimal acini (lumen marked by asterisks) treated with the cytoskeletal toxin cytochalasin D display an accumulation of syndapin II (B) close to the actin-rich (C) apical membrane; confocal images. Reproduced with permission from The American Society for Cell Biology (da Costa et al., 2003). (D) Differentiated C2F3 myotubes immunostained for the syndapin III isoform (image kindly provided by M. Plomann).