Chaperone-like activity of the AAA domain of the yeast Yme1 AAA protease

The AAA domain, a conserved Walker-type ATPase module, is a feature of memb ers of the AAA family of proteins(1,2), which are involved in many cellular processes, including vesicular transport(3-7), organelle biogenesis(8), mi crotubule rearrangement(9) and protein degradation(10-12), The function of the AAA domain, however, has not been explained. Membrane-anchored AAA prot eases of prokaryotic and eukaryotic cells comprise a subfamily of AAA prote ins(13-15) that have metal-dependent peptidase activity and mediate the deg radation of non-assembled membrane proteins. Inactivation of an orthologue of this protease family in humans causes neurodegeneration in hereditary sp astic paraplegia(16). Here we investigate the AAA domain of the yeast prote in Yme1, a subunit of the i-AAA protease located in the inner membrane of m itochondria(17,18). We show that Yme1 senses the folding state of solvent-e xposed domains and specifically degrades unfolded membrane proteins. Substr ate recognition and binding are mediated by the amino-terminal region of th e AAA domain. The purified AAA. domain of Yme1 binds unfolded polypeptides and suppresses their aggregation. Our results indicate that the AAA domain of Yme1 has a chaperone-like activity and suggest that the AAA domains of o ther AAA proteins may have a similar function.