Sly1 Binds to Golgi and ER Syntaxins via a Conserved N-Terminal Peptide Motif

Yamaguchi, Tomohiro; Dulubova, Irina; Min, Sang‐Won; Chen, Xiaocheng; Rizo, Josep; Südhof, Thomas C.

doi:10.1016/s1534-5807(02)00125-9

Cited by 186 publications

(290 citation statements)

References 59 publications

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“…Because the N-terminal sequence of various syntaxins has been previously implicated in interactions with SM proteins that are compatible with SNARE complex formation (20,21), we examined the role of the syntaxin-1A N-terminal sequence in the Munc18-1/SNARE complex interaction. Remarkably, SNARE complexes with a syntaxin-1A fragment containing a short N-terminal truncation (syntaxin-1A 10 -253 ) did not produce a significant shift in the mobility of Munc18-1 in gel filtration, showing that the syntaxin-1A N-terminal sequence is critical for binding of Munc18-1 to the SNARE complex (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies suggested that SNAREs and SM proteins interact by diverse mechanisms: Munc18-1 (and likely Munc18-2) was shown to bind only to the closed conformation of syntaxin outside of the SNARE complex (7,8,16); Sly1, Vps45, and Munc18c were found to bind to the N-terminal sequences of their respective cognate syntaxins independent of whether they are in SNARE complexes (20,21,25,26,33); yeast Sec1p was observed to bind only to assembled SNARE complexes without participation of the N-terminal sequence of syntaxins Sso1/2p (18,19); and Vps33p was found to bind to SNARE complexes by interacting with the PX domain of Vam7p (27,28). Faced with this diversity of interactions and the fact that, among SM proteins, only Munc18-1 did not bind to assembled SNARE complexes, we have reinvestigated how Munc18-1 interacts with SNARE proteins.…”

Section: Discussionmentioning

confidence: 99%

“…(ii) Sec1p binds to assembled SNARE complexes but not to the isolated syntaxin-1 homologues Sso1/2p (18,19). (iii) Sly1, Vps45, and Munc18c bind to short N-terminal sequences in their cognate syntaxins, an interaction that is compatible with either a closed conformation of syntaxin outside of a SNARE complex or an open conformation within a SNARE complex (20)(21)(22)(23)(24)(25)(26). (iv) Vps33 is part of the large HOPS complex that interacts with assembled SNARE complexes, at least in part by binding to the N-terminal PX domain of the SNARE protein Vam7p (27,28).…”

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confidence: 99%

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Munc18-1 binds directly to the neuronal SNARE complex

Dulubova¹,

Khvotchev²,

Liu³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Both SM proteins (for Sec1/Munc18-like proteins) and SNARE proteins (for soluble NSF-attachment protein receptors) are essential for intracellular membrane fusion, but the general mechanism of coupling between their functions is unclear, in part because diverse SM protein/SNARE binding modes have been described. During synaptic vesicle exocytosis, the SM protein Munc18-1 is known to bind tightly to the SNARE protein syntaxin-1, but only when syntaxin-1 is in a closed conformation that is incompatible with SNARE complex formation. We now show that Munc18-1 also binds tightly to assembled SNARE complexes containing syntaxin-1. The newly discovered Munc18-1/SNARE complex interaction involves contacts of Munc18-1 with the N-terminal H abc domain of syntaxin-1 and the four-helical bundle of the assembled SNARE complex. Together with earlier studies, our results suggest that binding of Munc18-1 to closed syntaxin-1 is a specialization that evolved to meet the strict regulatory requirements of neuronal exocytosis, whereas binding of Munc18-1 to assembled SNARE complexes reflects a general function of SM proteins involved in executing membrane fusion.exocytosis ͉ membrane fusion ͉ neurotransmitter release ͉ Sec1/Munc18-like proteins ͉ synapse E very eukaryotic cell relies on the precise and regulated trafficking of proteins, membranes, and other types of cargo between cellular compartments. The molecular machinery responsible for membrane traffic is partly conserved to provide for basic membrane fusion and fission reactions and is partly cell type-and compartment-specific to meet the unique requirements of a particular cellular locale (1). Neurons have arguably the most complex membrane trafficking of all cells, primarily because synaptic transmission requires continuous (but at the same time tightly regulated) synaptic membrane traffic. At a synapse, neurotransmitter release is effected by fusion of synaptic vesicles with the presynaptic plasma membrane. Synaptic vesicle fusion requires two conserved protein families that are universally involved in membrane fusion reactions: SNARE proteins, which are thought to pull membranes together by forming tight ''SNARE complexes,'' and Sec1/Munc18-like proteins (SM proteins), which perform an unknown but essential role in fusion and interact with SNARE proteins (reviewed in refs. 2-4).Synaptic vesicle exocytosis involves one SM protein (Munc18-1) and three SNARE proteins (synaptobrevin/VAMP on synaptic vesicles, and SNAP-25 and syntaxin-1A/1B on the plasma membrane; syntaxin-1A and -1B are highly homologous and thought to have identical functions). All SNARE proteins contain a conserved 60-to 70-residue sequence, the SNARE motif, that assembles into a four-helical bundle during SNARE complex formation (5). Synaptobrevin/VAMP and SNAP-25 are ''minimal SNARE proteins'' that are composed of one (synaptobrevin) or two (SNAP-25) SNARE motifs and a membraneanchor sequence. In syntaxin-1, however, the SNARE motif and transmembrane region occupy less than half of the sequence, with the...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Munc18-1 binds directly to the neuronal SNARE complex

Dulubova¹,

Khvotchev²,

Liu³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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365

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“…Because N-terminal regions in Sec22p and other SNARE proteins are required for their proper intracellular targeting (17)(18)(19)(20), it seems probable that signals within these regions will interact with distinct coat protein complexes in addition to COPII. Such differential interactions are likely to govern intracellular location and therefore contribute to the fidelity of membrane fusion reactions.…”

Section: Discussionmentioning

confidence: 99%

“…The N-terminal domains of SNARE proteins display significant diversity and appear to govern SNARE protein activity and distribution. For example, the N-terminal domain of the syntaxin-like SNARE proteins, such as neuronal syntaxin1 and yeast Sso1p, fold into three-helix bundles and inhibit SNARE pairing when folded back against their SNARE domains ( [17][18][19][20]. The structure of the N-terminal domain of a non-syntaxin yeast SNARE, Ykt6p, resembles the overall fold of the actin regulatory protein, profilin.…”

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confidence: 99%

Sec22p Export from the Endoplasmic Reticulum Is Independent of SNARE Pairing

Liu

Flanagan

Barlowe

2004

Journal of Biological Chemistry

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Molecularly distinct sets of SNARE proteins localize to specific intracellular compartments and catalyze membrane fusion events. Although their central role in membrane fusion is appreciated, little is known about the mechanisms by which individual SNARE proteins are targeted to specific organelles. Here we investigated functional domains in Sec22p that direct this SNARE protein to the endoplasmic reticulum (ER), to Golgi membranes, and into SNARE complexes with Bet1p, Bos1p, and Sed5p. A series of Sec22p deletion mutants were monitored in COPII budding assays, subcellular fractionation gradients, and SNARE complex immunoprecipitations. We found that the N-terminal "profilinlike" domain of Sec22p was required but not sufficient for COPII-dependent export of Sec22p from the ER. Interestingly, versions of Sec22p that lacked the N-terminal domain were assembled into ER/Golgi SNARE complexes. Analyses of Sec22p SNARE domain mutants revealed a second signal within the SNARE motif (between layers ؊4 and ؊1) that was required for efficient ER export. Other SNARE domain mutants that contained this signal were efficiently packaged into COPII vesicles but failed to assemble into SNARE complexes. Together these results indicated that SNARE complex formation is neither required nor sufficient for Sec22p packaging into COPII transport vesicles and subsequent targeting to the Golgi complex. We propose that the COPII budding machinery has a preference for unassembled ER/Golgi SNARE proteins.In eukaryotic cells, most intracellular membrane fusion processes are mediated by a related family of small proteins, called SNARE 1 (soluble NSF attachment protein receptors) proteins (1, 2). SNAREs share a conserved heptad repeat coiled coil sequence, called the SNARE domain, that is typically adjacent to a C-terminal-membrane bound region (3). Specific sets of SNARE domains assemble into parallel four-helix bundles forming the stable core of a SNARE protein complex (4 -6). Current membrane fusion models theorize that cognate sets of SNARE proteins provided from opposing membranes assemble into "trans" SNARE complexes and drive membrane bilayers together during fusion (2, 7).The assembly of cognate SNAREs has also been proposed to define the compartmental specificity of membrane fusion based on experiments showing that only specific combinations of SNARE proteins catalyze in vitro fusion when reconstituted into synthetic proteoliposomes (8 -10). However, this proposal remains debated given the promiscuity of SNARE interactions in vitro (11-13), functional redundancy in vivo (14, 15), and requirements for individual SNARE proteins in multiple intracellular membrane fusion steps (16). These and other observations suggest that additional spatial and temporal determinants in SNARE proteins contribute to the specificity of the membrane fusion (2). The N-terminal domains of SNARE proteins display significant diversity and appear to govern SNARE protein activity and distribution. For example, the N-terminal domain of the syntaxin-like SNARE prot...

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Neuronal SNARE complex assembly guided by Munc18‐1 and Munc13‐1

Wang

2022

FEBS Open Bio

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Neurotransmitter release by Ca2+‐triggered synaptic vesicle exocytosis is essential for information transmission in the nervous system. The soluble N‐ethylmaleimide sensitive factor attachment protein receptors (SNAREs) syntaxin‐1, SNAP‐25, and synaptobrevin‐2 form the SNARE complex to bring synaptic vesicles and the plasma membranes together and to catalyze membrane fusion. Munc18‐1 and Munc13‐1 regulate synaptic vesicle priming via orchestrating neuronal SNARE complex assembly. In this review, we summarize recent advances toward the functions and molecular mechanisms of Munc18‐1 and Munc13‐1 in guiding neuronal SNARE complex assembly, and discuss the functional similarities and differences between Munc18‐1 and Munc13‐1 in neurons and their homologs in other intracellular membrane trafficking systems.

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Sly1 Binds to Golgi and ER Syntaxins via a Conserved N-Terminal Peptide Motif

Cited by 186 publications

References 59 publications

Munc18-1 binds directly to the neuronal SNARE complex

Munc18-1 binds directly to the neuronal SNARE complex

Sec22p Export from the Endoplasmic Reticulum Is Independent of SNARE Pairing

Neuronal SNARE complex assembly guided by Munc18‐1 and Munc13‐1

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