Clamping Complexin the SNARE Complex and Is Displaced Domain to the Aligned Α-Helices of Complexin Binds Through Its Central Vesicles to the Membrane

CORBIS NATURE

REVIEWS

Molecular Clamping complexin the SNARE complex and is displaced domain to the aligned α-helices of complexin binds through its central vesicles to the membrane. Cytosolic and their interaction attaches synaptic vesicles and cell membranes, acts as a fusion enhancer. whereas its amino-terminal domain fusion clamp (preventing fusion), that its accessory helix acts as a structure of complexin and conclude groups have analysed the molecular lates neurotransmitter release. Two protein receptor) complex and regu the SNARE (soluble NSF-attachment The protein parallel manner. They proposed that sequences are aligned in an anti one of the SNAREs, when the two VAMP (also called synaptobrevin), of the membrane-proximal region of complexin is homologous to that sequence of the accessory helix of binding prior to membrane fusion. Ca on M Giraudo SNARE proteins are localized to 2+ EM c -activated synaptotagmin ell Biology b RANE et al. complexi found that the the that found dy n

- ublisher accessory helix were added at the was homologous to the complexin a recombinant VAMP peptide that was triggered when complexin and they showed that membrane fusion clamp. complex and thereby acts as a fusion the same binding site in the SNARE complexin competes with VAMP for an intact helix accessory was able to N-terminal 27 amino acids but had deletion mutant that lacked the but not the central domain). A lacked most of the helix accessory N terminus (and that therefore that lacked 40 amino acids at the complexin but not complexin by the addition of wild-type release. These wereeffects rescued events but impaired evoked synaptic increased spontaneous vesicle-fusion complexin with RNA interference cortical neurons. Knocking down of complexin in cultured mouse exerts the clamping function. the accessory helix of complexin that prevent fusion, confirming that it is were dominant-negative and did not the clamping ability of complexin mutations in this helix that reduced in the fusion assays. By contrast, resistant to VAMP competition clamping rendered complexin more in the helix accessory that enhanced hypothesis. Furthermore, mutations fusion did not occur, supporting the peptide was added after complexin, synaptotagmin. When the VAMP same time in the absence of Ca Using an Maximov s Limit ed. Allrights r in vitro in et al. studied the role Resea fusion assay, eserv ed

2+ and and

R ch highlights from VAMP-knockout mice that was introduced into cortical cultures but still forms SNARE complexes mutant that does not bind complexin evoked release. domains mediate spontaneous and events, and that different complexin tant for mediating membrane fusion acids of the N terminus are impor results suggest that the 27 amino impaired evoked response. These spontaneous release), but not the ous fusion events (that is, clamp rescue the phenotype of spontane the the domains of complexin. previously unknown task division for membrane-fusion events, revealing a are important for the activation of acids of the N terminus of complexin complex, and that the 27 amino with VAMP to bind to the SNARE as a fusion clamp, by competing accessory helix of complexin acts of SNAREs onto the membrane complexin acts on the force translation the same phenotype, indicating that (outside the SNARE complex) had VAMP inserts into the membrane Interestingly, a function by binding to VAMP. complexin executes its clamping were decreased. This indicates that VAMP, whereas evoked events those of cells expressing wild-type rescued and even elevated above spontaneous fusion events were lack spontaneous or evoked release, membranes in fusion. force transfer from SNARE complexes to (2009) | Maximov, A. SNARE-mediated fusion. et al. ORIGINAL RESEARCH PAPER Furthermore, when a VAMP These results suggest that the Alternative zippering as an on-off switch for Claudia Wiedemann, Chief Editor, Vol Nature Reviews Neuroscience UME point mutation where et al. Science Complexin controls the Science 10 10

323 | S

, 516–521 (2009) MARC 323 Giraudo, C. G. , 512–516 h .

2009 - -