DYRK1B mutations associated with metabolic syndrome impair the chaperone-dependent maturation of the kinase domain

Abstract Two missense mutations of the DYRK1B gene have recently been found to co-segregate with a rare autosomal-dominant form of metabolic syndrome. This gene encodes a member of the DYRK family of protein kinases, which depend on tyrosine autophosphorylation to acquire the catalytically active co...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Samira Abu Jhaisha, Esti W. Widowati, Isao Kii, Rie Sonamoto, Stefan Knapp, Chrisovalantis Papadopoulos, Walter Becker
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/780fbe1e29d44a888eddf2c261b76471
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:780fbe1e29d44a888eddf2c261b76471
record_format	dspace
spelling	oai:doaj.org-article:780fbe1e29d44a888eddf2c261b764712021-12-02T12:32:15ZDYRK1B mutations associated with metabolic syndrome impair the chaperone-dependent maturation of the kinase domain10.1038/s41598-017-06874-w2045-2322https://doaj.org/article/780fbe1e29d44a888eddf2c261b764712017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06874-whttps://doaj.org/toc/2045-2322Abstract Two missense mutations of the DYRK1B gene have recently been found to co-segregate with a rare autosomal-dominant form of metabolic syndrome. This gene encodes a member of the DYRK family of protein kinases, which depend on tyrosine autophosphorylation to acquire the catalytically active conformation. The mutations (H90P and R102C) affect a structural element named DYRK homology (DH) box and did not directly interfere with the conformation of the catalytic domain in a structural model of DYRK1B. Cellular assays showed that the mutations did not alter the specific activity of mature kinase molecules. However, a significant part of the mutant DYRK1B protein accumulated in detergent-insoluble cytoplasmic aggregates and was underphosphorylated on tyrosine. The mutant DYRK1B variants were more vulnerable to the HSP90 inhibitor ganetespib and showed enhanced binding to the co-chaperone CDC37 as compared to wild type DYRK1B. These results support the hypothesis that the mutations in the DH box interfere with the maturation of DYRK1B by tyrosine autophosphorylation and compromise the conformational stability of the catalytic domain, which renders the kinase susceptible to misfolding.Samira Abu JhaishaEsti W. WidowatiIsao KiiRie SonamotoStefan KnappChrisovalantis PapadopoulosWalter BeckerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Samira Abu Jhaisha Esti W. Widowati Isao Kii Rie Sonamoto Stefan Knapp Chrisovalantis Papadopoulos Walter Becker DYRK1B mutations associated with metabolic syndrome impair the chaperone-dependent maturation of the kinase domain
description	Abstract Two missense mutations of the DYRK1B gene have recently been found to co-segregate with a rare autosomal-dominant form of metabolic syndrome. This gene encodes a member of the DYRK family of protein kinases, which depend on tyrosine autophosphorylation to acquire the catalytically active conformation. The mutations (H90P and R102C) affect a structural element named DYRK homology (DH) box and did not directly interfere with the conformation of the catalytic domain in a structural model of DYRK1B. Cellular assays showed that the mutations did not alter the specific activity of mature kinase molecules. However, a significant part of the mutant DYRK1B protein accumulated in detergent-insoluble cytoplasmic aggregates and was underphosphorylated on tyrosine. The mutant DYRK1B variants were more vulnerable to the HSP90 inhibitor ganetespib and showed enhanced binding to the co-chaperone CDC37 as compared to wild type DYRK1B. These results support the hypothesis that the mutations in the DH box interfere with the maturation of DYRK1B by tyrosine autophosphorylation and compromise the conformational stability of the catalytic domain, which renders the kinase susceptible to misfolding.
format	article
author	Samira Abu Jhaisha Esti W. Widowati Isao Kii Rie Sonamoto Stefan Knapp Chrisovalantis Papadopoulos Walter Becker
author_facet	Samira Abu Jhaisha Esti W. Widowati Isao Kii Rie Sonamoto Stefan Knapp Chrisovalantis Papadopoulos Walter Becker
author_sort	Samira Abu Jhaisha
title	DYRK1B mutations associated with metabolic syndrome impair the chaperone-dependent maturation of the kinase domain
title_short	DYRK1B mutations associated with metabolic syndrome impair the chaperone-dependent maturation of the kinase domain
title_full	DYRK1B mutations associated with metabolic syndrome impair the chaperone-dependent maturation of the kinase domain
title_fullStr	DYRK1B mutations associated with metabolic syndrome impair the chaperone-dependent maturation of the kinase domain
title_full_unstemmed	DYRK1B mutations associated with metabolic syndrome impair the chaperone-dependent maturation of the kinase domain
title_sort	dyrk1b mutations associated with metabolic syndrome impair the chaperone-dependent maturation of the kinase domain
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/780fbe1e29d44a888eddf2c261b76471
work_keys_str_mv	AT samiraabujhaisha dyrk1bmutationsassociatedwithmetabolicsyndromeimpairthechaperonedependentmaturationofthekinasedomain AT estiwwidowati dyrk1bmutationsassociatedwithmetabolicsyndromeimpairthechaperonedependentmaturationofthekinasedomain AT isaokii dyrk1bmutationsassociatedwithmetabolicsyndromeimpairthechaperonedependentmaturationofthekinasedomain AT riesonamoto dyrk1bmutationsassociatedwithmetabolicsyndromeimpairthechaperonedependentmaturationofthekinasedomain AT stefanknapp dyrk1bmutationsassociatedwithmetabolicsyndromeimpairthechaperonedependentmaturationofthekinasedomain AT chrisovalantispapadopoulos dyrk1bmutationsassociatedwithmetabolicsyndromeimpairthechaperonedependentmaturationofthekinasedomain AT walterbecker dyrk1bmutationsassociatedwithmetabolicsyndromeimpairthechaperonedependentmaturationofthekinasedomain
_version_	1718394102445244416

DYRK1B mutations associated with metabolic syndrome impair the chaperone-dependent maturation of the kinase domain

Ejemplares similares