Sec1/Munc18 protein Vps33 binds to SNARE domains and the quaternary SNARE complex

Lobingier, Braden T.

doi:10.1091/mbc.e12-05-0343

Cited by 102 publications

(148 citation statements)

References 56 publications

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“…Our analyses on the Vam3 interaction of HOPS differ in some small but critical points from previous work on Vps33 (13,14). Although we observe similar interactions of HOPS with Ykt6 and assembled SNAREs (Ref.…”

Section: Discussioncontrasting

confidence: 82%

“…Segment of Vam3-Recent work of Merz and co-workers (13,21) nicely demonstrated the interaction of isolated Vps33 with vacuolar SNAREs and suggested that Vps33 facilitates the assembly of SNAREs. Because we would like to correlate the binding ability with fusion activity, we focused on the entire HOPS complex instead.…”

Section: Identification Of the H Abc Domain As The Main Hops Bindingmentioning

confidence: 94%

“…We could also observe binding to Vam7 or just its N-terminal PX domain, although we found no interaction to the Vam3. This was surprising because Vam3 seemed to bind purified Vps33 (13), and HOPS can be isolated with Vam3 from cells (13,22).…”

Section: Identification Of the H Abc Domain As The Main Hops Bindingmentioning

confidence: 99%

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The Habc Domain of the SNARE Vam3 Interacts with the HOPS Tethering Complex to Facilitate Vacuole Fusion

Lürick¹,

Kuhlee

Bröcker³

et al. 2015

Journal of Biological Chemistry

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Section: Discussioncontrasting

confidence: 82%

Section: Identification Of the H Abc Domain As The Main Hops Bindingmentioning

confidence: 94%

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The Habc Domain of the SNARE Vam3 Interacts with the HOPS Tethering Complex to Facilitate Vacuole Fusion

Lürick¹,

Kuhlee

Bröcker³

et al. 2015

Journal of Biological Chemistry

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“…Order-of-addition experiments show that Munc18-2 accelerates the formation cdV8-resistant SNARE complexes, therefore supporting a role of Munc18-2 in proof-reading trans-SNARE complexes (52,(55)(56)(57). Additionally, our data also suggest that Munc18-2 facilitates SNAREpin zippering similarly to other SM proteins (43,54,(58)(59)(60)(61)(62)(63). Thus, although the GPI anchor may be less effective than the transmembrane domain in transducing the energy of SNARE assembly to drive membrane fusion, the increased number of assembled STX11-GPI SNARE complexes generated in the presence of Munc18-2 likely cooperate, giving rise to a higher energetically favorable state that could be sufficient to destabilize the phospholipid bilayers and result in complete membrane fusion.…”

Section: Discussionsupporting

confidence: 75%

SM protein Munc18-2 facilitates transition of Syntaxin 11-mediated lipid mixing to complete fusion for T-lymphocyte cytotoxicity

Spessott

Sanmillan

McCormick

et al. 2017

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

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The atypical lipid-anchored Syntaxin 11 (STX11) and its binding partner, the Sec/Munc (SM) protein Munc18-2, facilitate cytolytic granule release by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Patients carrying mutations in these genes develop familial hemophagocytic lymphohistiocytosis, a primary immunodeficiency characterized by impaired lytic granule exocytosis. However, whether a SNARE such as STX11, which lacks a transmembrane domain, can support membrane fusion in vivo is uncertain, as is the precise role of Munc18-2 during lytic granule exocytosis. Here, using a reconstituted "flipped" cell-cell fusion assay, we show that lipidanchored STX11 and its cognate SNARE proteins mainly support exchange of lipids but not cytoplasmic content between cells, resembling hemifusion. Strikingly, complete fusion is stimulated by addition of wild-type Munc18-2 to the assay, but not of Munc18-2 mutants with abnormal STX11 binding. Our data reveal that Munc18-2 is not just a chaperone of STX11 but also directly contributes to complete membrane merging by promoting SNARE complex assembly. These results further support the concept that SM proteins in general are part of the core fusion machinery. This fusion mechanism likely contributes to other cell-type-specific exocytic processes such as platelet secretion.SNARE | Syntaxin 11 | Munc18-2 | CTL | SM protein

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“…Vps33, one of the HOPS subunits, is the vacuolar SM (Sec1/ mUNC-18 family) protein. HOPS has direct affinity for vacuolar SNAREs (14)(15)(16), and helps to catalyze SNARE complex assembly and the subsequent fusion (17).…”

mentioning

confidence: 99%

Sec17 can trigger fusion of trans -SNARE paired membranes without Sec18

Zick

Orr

Schwartz³

et al. 2015

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

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120

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Sec17 [soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein; α-SNAP] and Sec18 (NSF) perform ATP-dependent disassembly of cis-SNARE complexes, liberating SNAREs for subsequent assembly of trans-complexes for fusion. A mutant of Sec17, with limited ability to stimulate Sec18, still strongly enhanced fusion when ample Sec18 was supplied, suggesting that Sec17 has additional functions. We used fusion reactions where the four SNAREs were initially separate, thus requiring no disassembly by Sec18. With proteoliposomes bearing asymmetrically disposed SNAREs, tethering and trans-SNARE pairing allowed slow fusion. Addition of Sec17 did not affect the levels of trans-SNARE complex but triggered sudden fusion of trans-SNARE paired proteoliposomes. Sec18 did not substitute for Sec17 in triggering fusion, but ADP-or ATPγS-bound Sec18 enhanced this Sec17 function. The extent of the Sec17 effect varied with the lipid headgroup and fatty acyl composition of the proteoliposomes. Two mutants further distinguished the two Sec17 functions: Sec17 L291A,L292A did not stimulate Sec18 to disassemble cis-SNARE complex but triggered the fusion of trans-SNARE paired membranes. Sec17 F21S,M22S , with diminished apolar character to its hydrophobic loop, fully supported Sec18-mediated SNARE complex disassembly but had lost the capacity to stimulate the fusion of trans-SNARE paired membranes. To model the interactions of SNARE-bound Sec17 with membranes, we show that Sec17, but not Sec17 F21S,M22S , interacted synergistically with the soluble SNARE domains to enable their stable association with liposomes. We propose a model in which Sec17 binds to trans-SNARE complexes, oligomerizes, and inserts apolar loops into the apposed membranes, locally disturbing the lipid bilayer and thereby lowering the energy barrier for fusion.I ntracellular vesicular traffic between organelles is the basis of cell growth, hormone secretion, and neurotransmission. At each step of exocytic and endocytic trafficking, membranes dock and fuse, mixing their lipids and luminal contents while keeping them separate from the cytosol. Families of proteins, conserved from yeast to humans, mediate docking and fusion. Fusion requires Rab family GTPases and "effector" proteins that bind to a Rab in its active, GTP-bound state (1). Among the effectors are large, organelle-specific tethering complexes. Fusion requires SNARE proteins and their chaperones. SNAREs (2) are proteins that can "snare" (bind to) each other, in cis (when anchored to the same membrane) or in trans (when anchored to apposed, tethered membranes). SNAREs have a conserved "SNARE domain" with a characteristic heptad repeat. SNAREs are categorized as R-SNAREs if they have a central arginyl residue, or Qa-, Qb-, or Qc-SNAREs with a central glutamyl residue (3). SNAREs form RQaQbQc quaternary cis-or trans-SNARE complexes, which bind SNARE chaperones, including the Sec1/Munc18 family of SNARE binding proteins, and Sec18/NSF (N-ethylmaleimidesensitive factor), an AAA family ATPase that drives SNARE c...

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Sec1/Munc18 protein Vps33 binds to SNARE domains and the quaternary SNARE complex

Cited by 102 publications

References 56 publications

The Habc Domain of the SNARE Vam3 Interacts with the HOPS Tethering Complex to Facilitate Vacuole Fusion

The Habc Domain of the SNARE Vam3 Interacts with the HOPS Tethering Complex to Facilitate Vacuole Fusion

SM protein Munc18-2 facilitates transition of Syntaxin 11-mediated lipid mixing to complete fusion for T-lymphocyte cytotoxicity

Sec17 can trigger fusion of trans -SNARE paired membranes without Sec18

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