title: A stomatin dimer modulates the activity of acid-sensing ion channels.
abstract: Stomatin proteins oligomerize at membranes and have been implicated in ion channel regulation and membrane trafficking. To obtain mechanistic insights into their function, we determined three crystal structures of the conserved stomatin domain of mouse stomatin that assembles into a banana-shaped dimer. We show that dimerization is crucial for the repression of acid-sensing ion channel 3 (ASIC3) activity. A hydrophobic pocket at the inside of the concave surface is open in the presence of an internal peptide ligand and closes in the absence of this ligand, and we demonstrate a function of this pocket in the inhibition of ASIC3 activity. In one crystal form, stomatin assembles via two conserved surfaces into a cylindrical oligomer, and these oligomerization surfaces are also essential for the inhibition of ASIC3-mediated currents. The assembly mode of stomatin uncovered in this study might serve as a model to understand oligomerization processes of related membrane-remodelling proteins, such as flotillin and prohibitin.
authors: Max-Delbrück Center for Molecular Medicine, Crystallography Department, Berlin, Germany.
authors: Janko
authors: J
authors: Brand
authors: Ewan St J
authors: ES
authors: Smith
authors: David
authors: D
authors: Schwefel
authors: Liudmila
authors: L
authors: Lapatsina
authors: Kate
authors: K
authors: Poole
authors: Damir
authors: D
authors: Omerbašić
authors: Alexey
authors: A
authors: Kozlenkov
authors: Joachim
authors: J
authors: Behlke
authors: Gary R
authors: GR
authors: Lewin
authors: Oliver
authors: O
authors: Daumke
mesh_terms: D062565:Acid Sensing Ion Channels / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001798:Blood Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D019281:Dimerization; D005347:Fibroblasts; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D017434:Protein Structure, Tertiary; D051381:Rats
chemical_list: C568269:ASIC3 protein, rat; D062565:Acid Sensing Ion Channels; D001798:Blood Proteins; C488964:Stom protein, mouse; D008565:Membrane Proteins