New gadget in the membrane trafficking toolbox: A novel inhibitor of SNARE priming

Hagai Abeliovich

doi:10.1074/jbc.h119.011334

Abstract

NSF (N-ethylmaleimide sensitive factor) and its yeast counterpart Sec18 are highly conserved homohexameric proteins that play vital roles in eukaryotic membrane trafficking. Sec18 functions by disrupting SNARE complexes formed in cis, on the same membrane. However, the molecular mechanisms of this process are poorly understood, in large part due to the lack of selective, reversible inhibitors. A new study by Sparks et al. now reports a small molecule that appears to selectively inhibit Sec18 action in an in vitro assay. Their finding now paves the way to elucidate further details of Sec18-mediated SNARE priming.

Highlights

Intracellular membrane– bound compartments are a hallmark of eukaryotic cells
We know that NSF and Sec[18] are highly conserved ATPases that form homohexamers to interact with the SNAP receptor (SNARE) proteins (10)
To identify novel Sec[18] inhibitors, Sparks et al used an in silico screen to look for molecules that would interact with the phosphatidic acid (PA)-binding site on NSF, as the structure of this complex is known

Summary

Introduction

Intracellular membrane– bound compartments are a hallmark of eukaryotic cells. These compartments are in flux, such that material is constantly entering and exiting each compartment; this movement underlies essential processes such as synaptic transmission, hormone secretion, cell motility, antigen presentation, and endocytosis. 2 The abbreviations used are: SNARE, SNAP receptor; NEM, N-ethylmaleimide; NSF, N-ethylmaleimide sensitive factor; PA, phospholipid phosphatidic acid; IPA, inhibitor of priming activity. We know that NSF and Sec[18] are highly conserved ATPases that form homohexamers to interact with the SNARE proteins (10).

Results

Conclusion