Structure of mammalian plasma fetuin-B and its mechanism of selective metallopeptidase inhibition
- Publikationstyp:
- Zeitschriftenaufsatz
- Metadaten:
-
- Autoren
- Anna Cuppari
- Hagen Koerschgen
- Dirk Fahrenkamp
- Carlo Schmitz
- Tibisay Guevara
- Konstantin Karmilin
- Michael Kuske
- Mario Olf
- Eileen Dietzel
- Irene Yiallouros
- Daniele de Sanctis
- Theodoros Goulas
- Ralf Weiskirchen
- Willi Jahnen-Dechent
- Julia Floehr
- Walter Stoecker
- Luca Jovine
- F Xavier Gomis-Rueth
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000460412800019&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1107/S2052252519001568
- Externe Identifier
- Clarivate Analytics Document Solution ID: HN7ZM
- PubMed Identifier: 30867929
- ISSN
- 2052-2525
- Zeitschrift
- IUCRJ
- Schlüsselwörter
- mammalian fertilization
- sperm-egg fusion
- polyspermy
- metallopeptidase
- protein inhibitor
- structure determination
- protein structure
- X-ray crystallography
- enzyme mechanisms
- multi-protein complexes
- Paginierung
- 317 - 330
- Datum der Veröffentlichung
- 2019
- Status
- Published
- Titel
- Structure of mammalian plasma fetuin-B and its mechanism of selective metallopeptidase inhibition
- Sub types
- Article
- Ausgabe der Zeitschrift
- 6
Datenquelle: Web of Science (Lite)
- Andere Metadatenquellen:
-
- Abstract
- <jats:p>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 QWV<jats:italic>X</jats:italic>GP motif. The CY1 module assists in structural integrity and the CTR is not involved in inhibition, as verified by<jats:italic>in vitro</jats:italic>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 QWV<jats:italic>X</jats:italic>GP-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.</jats:p>
- Date of acceptance
- 2019
- Autoren
- Anna Cuppari
- Hagen Körschgen
- Dirk Fahrenkamp
- Carlo Schmitz
- Tibisay Guevara
- Konstantin Karmilin
- Michael Kuske
- Mario Olf
- Eileen Dietzel
- Irene Yiallouros
- Daniele de Sanctis
- Theodoros Goulas
- Ralf Weiskirchen
- Willi Jahnen-Dechent
- Julia Floehr
- Walter Stoecker
- Luca Jovine
- F Xavier Gomis-Rüth
- DOI
- 10.1107/s2052252519001568
- eISSN
- 2052-2525
- Ausgabe der Veröffentlichung
- 2
- Zeitschrift
- IUCrJ
- Online publication date
- 2019
- Paginierung
- 317 - 330
- Datum der Veröffentlichung
- 2019
- Status
- Published
- Herausgeber
- International Union of Crystallography (IUCr)
- Herausgeber URL
- http://dx.doi.org/10.1107/s2052252519001568
- Datum der Datenerfassung
- 2022
- Titel
- Structure of mammalian plasma fetuin-B and its mechanism of selective metallopeptidase inhibition
- Ausgabe der Zeitschrift
- 6
Datenquelle: Crossref
- Abstract
- Mammalian fetuin-A and fetuin-B are abundant serum proteins with pleiotropic functions. Fetuin-B is a highly selective and potent inhibitor of metallo-peptidases (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 QWV<i>X</i>GP motif. The CY1 module assists in structural integrity and the CTR is not involved in inhibition, as verified by <i>in vitro</i> 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 QWV<i>X</i>GP-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.
- Addresses
- Proteolysis Laboratory, Department of Structural Biology, Molecular Biology Institute of Barcelona, CSIC, Barcelona Science Park, Helix Building, c/o Baldiri Reixac 15-21, E-08028 Barcelona, Catalonia, Spain.
- Autoren
- Anna Cuppari
- Hagen Körschgen
- Dirk Fahrenkamp
- Carlo Schmitz
- Tibisay Guevara
- Konstantin Karmilin
- Michael Kuske
- Mario Olf
- Eileen Dietzel
- Irene Yiallouros
- Daniele de Sanctis
- Theodoros Goulas
- Ralf Weiskirchen
- Willi Jahnen-Dechent
- Julia Floehr
- Walter Stoecker
- Luca Jovine
- F Xavier Gomis-Rüth
- DOI
- 10.1107/s2052252519001568
- eISSN
- 2052-2525
- Externe Identifier
- PubMed Identifier: 30867929
- PubMed Central ID: PMC6400186
- Funding acknowledgements
- Johannes Gutenberg-Universität Mainz:
- Centrum för Innovativ Medicin:
- Medizinische Fakultät, RWTH Aachen University:
- Ministerio de Ciencia e Innovación: BFU2015-64487R
- European Molecular Biology Organization:
- Deutsche Forschungsgemeinschaft: FL1033/1
- Vetenskapsrådet:
- Deutsche Forschungsgemeinschaft: FA1518/1-1
- Ministerio de Ciencia e Innovación: MDM-2014-0435
- Departament d'Innovació, Universitats i Empresa, Generalitat de Catalunya: 2017SGR3
- Deutsche Forschungsgemeinschaft: JA562/16
- Open access
- true
- ISSN
- 2052-2525
- Ausgabe der Veröffentlichung
- Pt 2
- Zeitschrift
- IUCrJ
- Sprache
- eng
- Medium
- Electronic-eCollection
- Online publication date
- 2019
- Open access status
- Open Access
- Paginierung
- 317 - 330
- Datum der Veröffentlichung
- 2019
- Status
- Published
- Publisher licence
- CC BY
- Datum der Datenerfassung
- 2019
- Titel
- Structure of mammalian plasma fetuin-B and its mechanism of selective metallopeptidase inhibition.
- Sub types
- research-article
- Journal Article
- Ausgabe der Zeitschrift
- 6
Files
https://journals.iucr.org/m/issues/2019/02/00/jt5031/jt5031.pdf https://europepmc.org/articles/PMC6400186?pdf=render
Datenquelle: Europe PubMed Central
- Abstract
- Mammalian fetuin-A and fetuin-B are abundant serum proteins with pleiotropic functions. Fetuin-B is a highly selective and potent inhibitor of metallo-peptidases (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.
- Date of acceptance
- 2019
- Autoren
- Anna Cuppari
- Hagen Körschgen
- Dirk Fahrenkamp
- Carlo Schmitz
- Tibisay Guevara
- Konstantin Karmilin
- Michael Kuske
- Mario Olf
- Eileen Dietzel
- Irene Yiallouros
- Daniele de Sanctis
- Theodoros Goulas
- Ralf Weiskirchen
- Willi Jahnen-Dechent
- Julia Floehr
- Walter Stoecker
- Luca Jovine
- F Xavier Gomis-Rüth
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/30867929
- DOI
- 10.1107/S2052252519001568
- Externe Identifier
- PubMed Central ID: PMC6400186
- ISSN
- 2052-2525
- Ausgabe der Veröffentlichung
- Pt 2
- Zeitschrift
- IUCrJ
- Schlüsselwörter
- X-ray crystallography
- enzyme mechanisms
- mammalian fertilization
- metallopeptidase
- multi-protein complexes
- polyspermy
- protein inhibitor
- protein structure
- sperm–egg fusion
- structure determination
- Sprache
- eng
- Country
- England
- Paginierung
- 317 - 330
- PII
- jt5031
- Datum der Veröffentlichung
- 2019
- Status
- Published online
- Titel
- Structure of mammalian plasma fetuin-B and its mechanism of selective metallopeptidase inhibition.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 6
Datenquelle: PubMed
- Author's licence
- CC-BY
- Autoren
- Anna Cuppari
- Hagen Körschgen
- Dirk Fahrenkamp
- Carlo Schmitz
- Tibisay Guevara
- Konstantin Karmilin
- Michael Kuske
- Mario Olf
- Eileen Dietzel
- Irene Yiallouros
- Daniele de Sanctis
- Theodoros Goulas
- Ralf Weiskirchen
- Willi Jahnen-Dechent
- Julia Floehr
- Walter Stöcker
- Luca Jovine
- F Xavier Gomis-Rüth
- Hosting institution
- Universitätsbibliothek Mainz
- Sammlungen
- JGU-Publikationen
- Resource version
- Published version
- URN
- urn:nbn:de:hebis:77-publ-590308
- DOI
- 10.1107/S2052252519001568
- Funding acknowledgements
- DFG, Open Access-Publizieren Universität Mainz / Universitätsmedizin
- File(s) embargoed
- false
- Open access
- true
- ISSN
- 2052-2525
- Ausgabe der Veröffentlichung
- 2
- Zeitschrift
- IUCrJ
- Schlüsselwörter
- 570 Biowissenschaften
- 570 Life sciences
- Sprache
- eng
- Open access status
- Open Access
- Paginierung
- 317 - 330
- Datum der Veröffentlichung
- 2019
- Public URL
- https://openscience.ub.uni-mainz.de/handle/20.500.12030/770
- Herausgeber
- International Union of Crystallography
- Herausgeber URL
- http://dx.doi.org/10.1107/S2052252519001568
- Datum der Datenerfassung
- 2019
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2019
- Zugang
- Public
- Titel
- Structure of mammalian plasma fetuin-B and its mechanism of selective metallopeptidase inhibition
- Ausgabe der Zeitschrift
- 6
Files
59030.pdf
Datenquelle: OPENSCIENCE.UB
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