AMSH (associated molecule with the Src homology 3 domain (SH3) of STAM (signal-transducing adapter molecule, also known as STAMBP)) and AMSH-like proteins (AMSH-LP) are members of JAMM/MPN+ deubiquitinases (DUBs), with Zn2+-dependent ubiquitin isopeptidase activity. AMSH specifically cleaves Lys 63 and not Lys48-linked polyubiquitin (poly-Ub) chains, thus facilitating the recycling and subsequent trafficking of receptors to the cell surface. AMSH and AMSH-LP are anchored on the early endosomal membrane via interaction with the clathrin coat. AMSH shares a common SH3-binding site with another endosomal DUB, UBPY (ubiquitin-specific protease Y; also known as USP8), the latter being a cysteine protease that does not discriminate between Lys48 and Lys63-linked ubiquitin. AMSH is involved in the degradation of EGF receptor (EGFR) and possibly other ubiquitinated endocytosed proteins. AMSH also interacts with CHMP1, CHMP2, and CHMP3 proteins, all of which are components of ESCRT-III, suggested to be required for EGFR down-regulation. The function of AMSH-LP has not been elucidated; however, it exhibits two fundamentally distinct features from AMSH: first, there is a substitution in the critical amino acid residue in the SH3-binding motif (SBM) in the human AMSH-LP, but not in its mouse ortholog, and lacks STAM-binding ability; second, AMSH-LP lacks the ability to interact with CHMP proteins. It is therefore likely that AMSH and AMSH-LP play different roles on early endosomes.
Structure:2ZNR: Human AMSH-like protein (AMSH-LP); contacts calculated at 4.0A. - View structure with Cn3D
Comment:AMSH (associated molecule with the SH3 domain of STAM) family protein, termed AMSH-like protein (AMSH-LP), is a deubiqutinating enzyme (DUB) and a zinc metalloprotease. It's catalytic and metal binding residues have also been determined experimentally.