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-associated proteins, such as flotillin and prohibitin.
Brand, J., Smith, E.S., Schwefel, D., Lapatsina, L., Poole, K., Omerbašić, D., Kozlenkov, A., Behlke, J., Lewin, G.R., Daumke, O. (2012) A stomatin dimer modulates the activity of acid-sensing ion channels. EMBO J 31, 363546-46
Researcher in my group
Janko Brand (PhD 2012)
Gary Lewin, Kate Poole (MDC).
Figure 1: a) Crystal structure of the stomatin dimer. b) ASIC3 channels expressed in CHO cells show acid-induced ion currents. Co-expression of stomatin with ASIC3 interferes with these currents. Mutations in the stomatin dimer interface completely abrogate the modulation of ASIC3 function (here not shown). c) Based on crystal contacts and mutagenesis, we proposed a ring-like oligomeric model for stomatin.