In:
Biological Chemistry, Walter de Gruyter GmbH, Vol. 398, No. 9 ( 2017-08-28), p. 975-994
Abstract:
Peptidases 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 α 2 -macroglobulin inhibitor family (α 2 Ms) 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 α 2 Ms, which use ‘Venus-flytrap’ and ‘snap-trap’ mechanisms, respectively. In the former, represented by archetypal human α 2 M, 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 α 2 M from Escherichia coli , covalent linkage and steric hindrance of the prey inhibit activity, but only against very large substrates.
Type of Medium:
Online Resource
ISSN:
1437-4315
,
1431-6730
DOI:
10.1515/hsz-2016-0329
Language:
Unknown
Publisher:
Walter de Gruyter GmbH
Publication Date:
2017
detail.hit.zdb_id:
1466062-3
SSG:
12
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