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Título

Structural and functional insight into pan-endopeptidase inhibition by α2-macroglobulins

AutorGoulas, Theodoros CSIC ORCID; García Ferrer, Irene CSIC; Marrero, Aniebrys CSIC; Marino-Puertas, Laura CSIC ; Duquerroy, Stéphane; Gomis-Rüth, F. Xavier CSIC ORCID
Palabras claveBait region cleavage
Conformational rearrangement
Irreversible inhibition
Multi-domain protein
Protein inhibitor
Regulation of proteolytic activity
Fecha de publicaciónsep-2017
EditorWalter de Gruyter
CitaciónBiological Chemistry 398(9): 975–994 (2017)
ResumenPeptidases must be exquisitely regulated to prevent erroneous cleavage and one control is provided by protein inhibitors. These are usually specific for particular peptidases or families and sterically block the active-site cleft of target enzymes using lock-and-key mechanisms. In contrast, members of the +1400-residue multi-domain α2-macroglobulin inhibitor family (α2Ms) are directed against a broad spectrum of endopeptidases of disparate specificities and catalytic types, and they inhibit their targets without disturbing their active sites. This is achieved by irreversible trap mechanisms resulting from large conformational rearrangement upon cleavage in a promiscuous bait region through the prey endopeptidase. After decades of research, high-resolution structural details of these mechanisms have begun to emerge for tetrameric and monomeric α2Ms, which use ‘Venus-flytrap’ and ‘snap-trap’ mechanisms, respectively. In the former, represented by archetypal human α2M, inhibition is exerted through physical entrapment in a large cage, in which preys are still active against small substrates and inhibitors that can enter the cage through several apertures. In the latter, represented by a bacterial α2M from Escherichia coli, covalent linkage and steric hindrance of the prey inhibit activity, but only against very large substrates.
Versión del editorhttps://doi.org/10.1515/hsz-2016-0329
URIhttp://hdl.handle.net/10261/174234
DOI10.1515/hsz-2016-0329
ISSN1431-6730
E-ISSN1437-4315
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