Multiple binding proteins suggest diverse functions for the N-ethylmaleimide sensitive factor.
The hexameric ATPase, N-ethylmaleimide sensitive factor (NSF), is essential to vesicular transport and membrane fusion because it affects the conformations and associations of the soluble NSF attachment protein receptor (SNARE) proteins. NSF binds SNAREs through adaptors called soluble NSF attachment proteins (alpha- or beta-SNAP) and disassembles SNARE complexes to recycle the monomers. NSF contains three domains, two nucleotide-binding domains (NSF-D1 and -D2) and an amino terminal domain (NSF-N) that is required for SNAP-SNARE complex binding. Mutagenesis studies indicate that a cleft between the two sub-domains of NSF-N is critical for binding. The structural conservation of N domains in NSF, p97/VCP, and VAT suggests that a similar type of binding site could mediate substrate recognition by other AAA proteins. In addition to SNAP-SNARE complexes, NSF also binds other proteins and protein complexes such as AMPA receptor subunits (GluR2), beta2-adrenergic receptor, beta-Arrestin1, GATE-16, LMA1, rabs, and rab-containing complexes. The potential for these interactions indicates a broader role for NSF in the assembly/disassembly cycles of several cellular complexes and suggests that NSF may have specific regulatory effects on the functions of the proteins involved in these complexes. The structural requirements for these interactions and their physiological significance will be discussed.
Whiteheart
Sidney W
SW
Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, 800 Rose Street, Lexington, KY 40536, USA. whitehe@pop.uky.edu
Matveeva
Elena A
EA
D001665:Binding Sites; D046911:Macromolecular Substances; D052066:N-Ethylmaleimide-Sensitive Proteins; D011485:Protein Binding; D050600:SNARE Proteins; D033921:Vesicular Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*
D046911:Macromolecular Substances; D050600:SNARE Proteins; D033921:Vesicular Transport Proteins; D052066:N-Ethylmaleimide-Sensitive Proteins