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Authors: Cuppari, Anna
Körschgen, Hagen
Fahrenkamp, Dirk
Schmitz, Carlo
Guevara, Tibisay
Karmilin, Konstantin
Kuske, Michael
Olf, Mario
Dietzel, Eileen
Yiallouros, Irene
de Sanctis, Daniele
Goulas, Theodoros
Weiskirchen, Ralf
Jahnen-Dechent, Willi
Floehr, Julia
Stöcker, Walter
Jovine, Luca
Gomis-Rüth, F. Xavier
Title: Structure of mammalian plasma fetuin-B and its mechanism of selective metallopeptidase inhibition
Online publication date: 12-Apr-2019
Year of first publication: 2019
Language: english
Abstract: Mammalian fetuin-A and fetuin-B are abundant serum proteins with pleiotropic functions. Fetuin-B is a highly selective and potent inhibitor of metallo­peptidases (MPs) of the astacin family, which includes ovastacin in mammals. By inhibiting ovastacin, fetuin-B is essential for female fertility. The crystal structure of fetuin-B was determined unbound and in complex with archetypal astacin, and it was found that the inhibitor has tandem cystatin-type modules (CY1 and CY2). They are connected by an exposed linker with a rigid, disulfide-linked CPDCP-trunk', and are followed by a C-terminal region (CTR) with little regular secondary structure. The CPDCP-trunk and a hairpin of CY2 form a bipartite wedge, which slots into the active-site cleft of the MP. These elements occupy the nonprimed and primed sides of the cleft, respectively, but spare the specificity pocket so that the inhibitor is not cleaved. The aspartate in the trunk blocks the catalytic zinc of astacin, while the CY2 hairpin binds through a QWVXGP motif. The CY1 module assists in structural integrity and the CTR is not involved in inhibition, as verified by in vitro studies using a cohort of mutants and variants. Overall, the inhibition conforms to a novel raised-elephant-trunk' mechanism for MPs, which is reminiscent of single-domain cystatins that target cysteine peptidases. Over 200 sequences from vertebrates have been annotated as fetuin-B, underpinning its ubiquity and physiological relevance; accordingly, sequences with conserved CPDCP- and QWVXGP-derived motifs have been found from mammals to cartilaginous fishes. Thus, the raised-elephant-trunk mechanism is likely to be generally valid for the inhibition of astacins by orthologs of fetuin-B.
DDC: 570 Biowissenschaften
570 Life sciences
Institution: Johannes Gutenberg-Universität Mainz
Department: FB 10 Biologie
Place: Mainz
URN: urn:nbn:de:hebis:77-publ-590308
Version: Published version
Publication type: Zeitschriftenaufsatz
License: CC BY
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Journal: IUCrJ
Pages or article number: 317
Publisher: International Union of Crystallography
Publisher place: Chester
Issue date: 2019
ISSN: 2052-2525
Publisher URL:
Publisher DOI: 10.1107/S2052252519001568
Appears in collections:JGU-Publikationen

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