7q60
From Proteopedia
Structure of TEV cleaved A2ML1 (A2ML1-TE)
Structural highlights
DiseaseA2ML1_HUMAN Disease susceptibility is associated with variants affecting the gene represented in this entry. FunctionA2ML1_HUMAN Is able to inhibit all four classes of proteinases by a unique 'trapping' mechanism. This protein has a peptide stretch, called the 'bait region' which contains specific cleavage sites for different proteinases. When a proteinase cleaves the bait region, a conformational change is induced in the protein which traps the proteinase. The entrapped enzyme remains active against low molecular weight substrates (activity against high molecular weight substrates is greatly reduced). Following cleavage in the bait region a thioester bond is hydrolyzed and mediates the covalent binding of the protein to the proteinase (By similarity). Displays inhibitory activity against chymotrypsin, papain, thermolysin, subtilisin A and, to a lesser extent, elastase but not trypsin. May play an important role during desquamation by inhibiting extracellular proteases.[UniProtKB:P01023][1] Publication Abstract from PubMedA2ML1 is a monomeric protease inhibitor belonging to the A2M superfamily of protease inhibitors and complement factors. Here, we investigate the protease-inhibitory mechanism of human A2ML1 and determine the structures of its native and protease-cleaved conformations. The functional inhibitory unit of A2ML1 is a monomer that depends on covalent binding of the protease (mediated by A2ML1's thioester) to achieve inhibition. In contrast to the A2M tetramer which traps proteases in two internal chambers formed by four subunits, in protease-cleaved monomeric A2ML1 disordered regions surround the trapped protease and may prevent substrate access. In native A2ML1, the bait region is threaded through a hydrophobic channel, suggesting that disruption of this arrangement by bait region cleavage triggers the extensive conformational changes that result in protease inhibition. Structural comparisons with complement C3/C4 suggest that the A2M superfamily of proteins share this mechanism for the triggering of conformational change occurring upon proteolytic activation. Cryo-EM structures of human A2ML1 elucidate the protease-inhibitory mechanism of the A2M family.,Nielsen NS, Zarantonello A, Harwood SL, Jensen KT, Kjoge K, Thogersen IB, Schauser L, Karlsen JL, Andersen GR, Enghild JJ Nat Commun. 2022 May 31;13(1):3033. doi: 10.1038/s41467-022-30758-x. PMID:35641520[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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