A quaternary tetramer assembly inhibits the deubiquitinating activity of USP25
Liu, Bing (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Sureda-Gómez, Marta (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Zhen, Yang (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Amador, Virginia (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Reverter i Cendrós, David (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Date:	2018
Abstract:	USP25 deubiquitinating enzyme is a key member of the ubiquitin system, which acts as a positive regulator of the Wnt/β-catenin signaling by promoting the deubiquitination and stabilization of tankyrases. USP25 is characterized by the presence of a long insertion in the middle of the conserved catalytic domain. The crystal structure of USP25 displays an unexpected homotetrameric quaternary assembly that is directly involved in the inhibition of its enzymatic activity. The tetramer is assembled by the association of two dimers and includes contacts between the coiled-coil insertion domain and the ubiquitin-binding pocket at the catalytic domain, revealing a distinctive autoinhibitory mechanism. Biochemical and kinetic assays with dimer, tetramer and truncation constructs of USP25 support this mechanism, displaying higher catalytic activity in the dimer assembly. Moreover, the high stabilization of tankyrases in cultured cells by ectopic expression of a constitutive dimer of USP25 supports a biological relevance of this tetramerization/inhibition mechanism.
Grants:	Ministerio de Economía y Competitividad BFU2015-66417-P Ministerio de Economía y Competitividad BFU2015-64879-R
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Amino acid sequence ; Catalytic domain ; Crystallography, X-Ray ; Enzyme stability ; Escherichia coli ; HEK293 cells ; Humans ; Kinetics ; Models, Biological ; Protein multimerization ; Protein structure, Secondary ; Recombinant proteins ; Tankyrases ; Ubiquitin thiolesterase
Published in:	Nature communications, Vol. 9 (2018) , art. 4973, ISSN 2041-1723

DOI: 10.1038/s41467-018-07510-5
PMID: 30478318

13 p, 2.3 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Biotecnologia i de Biomedicina (IBB)
Articles > Research articles
Articles > Published articles