Focus Group 2016

brief descriptions of the papers

Sollner et al Cell 1993

This was a key Rothman paper where they first elaborated the SNARE hypothesis based mainly on biochemical results with purified constituents associated with vesicle fusion. Ultimately, the proposed SNARE mechanism was completely backwards, but it paved the way for the correct form of the SNARE hypothesis.

Bullough et al Nature 1994

The first and best studied membrane fusion protein is hemagglutinin. After endocytosis of an influenza virus, the drop in pH triggers a massive conformational change in hemagglutinin that ultimately allows it to drive fusion of the viral envelop with the endosomal membrane thereby releasing the nucleocapsid into the cytoplasm. This paper from Don Wiley's group solved the structure of hemagglutinin's pH-triggered conformational change and provided a deep insight into the mechanism of protein-driven membrane fusion with the so-called 'hairpin model.'

Weber et al Cell 1998

The first demonstration that SNAREs were sufficient for fusion using recombinant v- and t-SNAREs reconstituted into liposomes. Rothman's group proposed that, in analogy with the hemagglutinin hairpin model, cognate SNAREs assemble as a 'SNAREpin' with a similar structure.

Zhao et al Nature 2015

Here, a cryo-EM structure of NSF, SNAPs, and SNARE complex (from Axel Brunger’s lab) provides a detailed model for how NSF disassembles the fully zippered SNARE complex, thereby separating the individual components. Structures captured with ATP vs ADP provide mechanistic hints as to how NSF/SNAP complexes can unwind many different types of SNARE isoforms.

Min et al Nat. Comm. 2013

This single-molecule study uses magnetic tweezers to monitor the energetics of SNARE assembly/disassembly. The authors discover a hysteresis in cycling between unzipped and rezipped complexes and propose that this provides a rectification to give directionality and net force production to the SNARE assembly.

Krishnakumar et al NSMB 2011

Complexin is a small cytoplasmic protein that directly binds the ternary SNARE complex. The role of complexin in regulating vesicle fusion has been the subject of much controversy and numerous conflicting models exist. This study proposes that complexin acts like a switch that permits synaptotagmin to trigger fusion.

Yang et al NSMB 2015

The first crystal structure of the Munc13 MUN domain provides insights into the hypothesis that Munc13’s MUN domain drives a closed-to-open transition in Syntaxin thereby catalyzing the initial assembly of the SNARE complex.

Hui et al Cell 2009

This study combines biochemical, EM, and electrophysiological approaches to investigate the role of synaptotagmin in bending lipid membranes as part of its role in the fusion mechanism.

Ma et al Science 2013

In this study from Jose Rizo’s group, a combination of NMR spectroscopy and proteoliposome fusion assay approaches is used to propose a new version of the SNARE hypothesis where Munc18 and Munc13 are now essential for the fusion process. One of the biggest puzzles still left in the field is why Munc18 and Munc13 are essential fusion proteins in vivo but totally dispensable in vitro. Perhaps this will prove to be a step in the right direction.

Baker et al Science 2015

A new structure of yeast homologs for VAMP and Munc18 from the Hughson lab suggests a mechanism for Munc18 in promoting the assembly of the SNARE complex. This study relies on a crystal structure, yeast biology, and in vitro proteoliposome fusion assays, and provides the first molecular model of Munc18 as a catalyst for SNARE assembly.