Enlightening molecular mechanisms through study of protein interactions.
Rizo J, Rosen MK, Gardner KH.
J Mol Cell Biol. 2012 Oct;4(5):270-83.
Free PMC Article

Abstract
The investigation of molecular mechanisms is a fascinating area of current biological research that unites efforts from scientists with very diverse expertise. This review provides a perspective on the characterization of protein interactions as a central aspect of this research. We discuss case studies on the neurotransmitter release machinery that illustrate a variety of principles and emphasize the power of combining nuclear magnetic resonance (NMR) spectroscopy with other biophysical techniques, particularly X-ray crystallography. These studies have shown that: (i) the soluble SNAP receptor (SNARE) proteins form a tight complex that brings the synaptic vesicle and plasma membranes together, which is key for membrane fusion; (ii) the SNARE syntaxin-1 adopts an autoinhibitory closed conformation; (iii) Munc18-1 plays crucial functions through interactions with closed syntaxin-1 and with the SNARE complex; (iv) Munc13s mediate the opening of syntaxin-1; (v) complexins play dual roles through distinct interactions with the SNARE complex; (vi) synaptotagmin-1 acts a Ca(2+) sensor, interacting simultaneously with the membranes and the SNAREs; and (vii) a Munc13 homodimer to Munc13-RIM heterodimer switch modulates neurotransmitter release. Overall, this research underlines the complexities involved in elucidating molecular mechanisms and how these mechanisms can depend critically on an interplay between strong and weak protein interactions.

Structure and function of SNARE and SNARE-interacting proteins.
Brunger AT.
Q Rev Biophys. 2005 Feb;38(1):1-47. (pdf linked in lecture)

Abstract
This review focuses on the so-called SNARE (soluble N-ethyl maleimide sensitive factor attachment protein receptor) proteins that are involved in exocytosis at the pre-synpatic plasma membrane. SNAREs play a role in docking and fusion of synaptic vesicles to the active zone, as well as in the Ca2+-triggering step itself, most likely in combination with the Ca2+ sensor synaptotagmin. Different SNARE domains are involved in different processes, such as regulation, docking, and fusion. SNAREs exhibit multiple configurational, conformational, and oliogomeric states. These different states allow SNAREs to interact with their matching SNARE partners, auxiliary proteins, or with other SNARE domains, often in a mutually exclusive fashion. SNARE core domains undergo progressive disorder to order transitions upon interactions with other proteins, culminating with the fully folded post-fusion (cis) SNARE complex. Physiological concentrations of neuronal SNAREs can juxtapose membranes, and promote fusion in vitro under certain conditions. However, significantly more work will be required to reconstitute an in vitro system that faithfully mimics the Ca2+-triggered fusion of a synaptic vesicle at the active zone.