Bipartite binding of the N terminus of Skp2 to cyclin A.
CDK
E3 ligase
E3 ubiquitin ligase
SCF
Skp2
cell cycle
crystal structure
cyclin
kinase
Journal
Structure (London, England : 1993)
ISSN: 1878-4186
Titre abrégé: Structure
Pays: United States
ID NLM: 101087697
Informations de publication
Date de publication:
02 09 2021
02 09 2021
Historique:
received:
24
02
2021
revised:
06
04
2021
accepted:
23
04
2021
pubmed:
15
5
2021
medline:
17
3
2022
entrez:
14
5
2021
Statut:
ppublish
Résumé
Skp2 and cyclin A are cell-cycle regulators that control the activity of CDK2. Cyclin A acts as an activator and substrate recruitment factor of CDK2, while Skp2 mediates the ubiquitination and subsequent destruction of the CDK inhibitor protein p27. The N terminus of Skp2 can interact directly with cyclin A but is not required for p27 ubiquitination. To gain insight into this poorly understood interaction, we have solved the 3.2 Å X-ray crystal structure of the N terminus of Skp2 bound to cyclin A. The structure reveals a bipartite mode of interaction with two motifs in Skp2 recognizing two discrete surfaces on cyclin A. The uncovered binding mechanism allows for a rationalization of the inhibitory effect of Skp2 on CDK2-cyclin A kinase activity toward the RxL motif containing substrates and raises the possibility that other intermolecular regulators and substrates may use similar non-canonical modes of interaction for cyclin targeting.
Identifiants
pubmed: 33989513
pii: S0969-2126(21)00127-1
doi: 10.1016/j.str.2021.04.011
pmc: PMC8419023
mid: NIHMS1705908
pii:
doi:
Substances chimiques
Cyclin A
0
S-Phase Kinase-Associated Proteins
0
SKP2 protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
975-988.e5Subventions
Organisme : NIGMS NIH HHS
ID : P30 GM124165
Pays : United States
Organisme : CIHR
ID : FDN-143277
Pays : Canada
Informations de copyright
Copyright © 2021 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests F.S. is a founder and consultant of Repare Therapeutics.
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