XLOS-observed mutations of MID1 Bbox1 domain cause domain unfolding.

MID1 catalyzes the ubiquitination of the protein alpha4 and the catalytic subunit of protein phosphatase 2A. Mutations within the MID1 Bbox1 domain are associated with X-linked Opitz G syndrome (XLOS). Our functional assays have shown that mutations of Ala130 to Val or Thr, Cys142 to Ser and Cys145...

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Autores principales:	Katharine M Wright, Kuanlin Wu, Omotolani Babatunde, Haijuan Du, Michael A Massiah
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e2773c44394b438ab2c5905c4abf4f0b
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spelling	oai:doaj.org-article:e2773c44394b438ab2c5905c4abf4f0b2021-11-25T06:00:53ZXLOS-observed mutations of MID1 Bbox1 domain cause domain unfolding.1932-620310.1371/journal.pone.0107537https://doaj.org/article/e2773c44394b438ab2c5905c4abf4f0b2014-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0107537https://doaj.org/toc/1932-6203MID1 catalyzes the ubiquitination of the protein alpha4 and the catalytic subunit of protein phosphatase 2A. Mutations within the MID1 Bbox1 domain are associated with X-linked Opitz G syndrome (XLOS). Our functional assays have shown that mutations of Ala130 to Val or Thr, Cys142 to Ser and Cys145 to Thr completely disrupt the polyubiquitination of alpha4. Using NMR spectroscopy, we characterize the effect of these mutations on the tertiary structure of the Bbox1 domain by itself and in tandem with the Bbox2 domain. The mutation of either Cys142 or Cys145, each of which is involved in coordinating one of the two zinc ions, results in the collapse of signal dispersion in the HSQC spectrum of the Bbox1 domain indicating that the mutant protein structure is unfolded. Each mutation caused the coordination of both zinc ions, which are ∼ 13 Å apart, to be lost. Although Ala130 is not involved in the coordination of a zinc ion, the Ala130Thr mutant Bbox1 domain yields a poorly dispersed HSQC spectrum similar to those of the Cys142Ser and Cys145Thr mutants. Interestingly, neither cysteine mutation affects the structure of the adjacent Bbox2 domain when the two Bbox domains are engineered in their native tandem Bbox1-Bbox2 protein construct. Dynamic light scattering measurements suggest that the mutant Bbox1 domain has an increased propensity to form aggregates compared to the wild type Bbox1 domain. These studies provide insight into the mechanism by which mutations observed in XLOS affect the structure and function of the MID1 Bbox1 domain.Katharine M WrightKuanlin WuOmotolani BabatundeHaijuan DuMichael A MassiahPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 9, p e107537 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Katharine M Wright Kuanlin Wu Omotolani Babatunde Haijuan Du Michael A Massiah XLOS-observed mutations of MID1 Bbox1 domain cause domain unfolding.
description	MID1 catalyzes the ubiquitination of the protein alpha4 and the catalytic subunit of protein phosphatase 2A. Mutations within the MID1 Bbox1 domain are associated with X-linked Opitz G syndrome (XLOS). Our functional assays have shown that mutations of Ala130 to Val or Thr, Cys142 to Ser and Cys145 to Thr completely disrupt the polyubiquitination of alpha4. Using NMR spectroscopy, we characterize the effect of these mutations on the tertiary structure of the Bbox1 domain by itself and in tandem with the Bbox2 domain. The mutation of either Cys142 or Cys145, each of which is involved in coordinating one of the two zinc ions, results in the collapse of signal dispersion in the HSQC spectrum of the Bbox1 domain indicating that the mutant protein structure is unfolded. Each mutation caused the coordination of both zinc ions, which are ∼ 13 Å apart, to be lost. Although Ala130 is not involved in the coordination of a zinc ion, the Ala130Thr mutant Bbox1 domain yields a poorly dispersed HSQC spectrum similar to those of the Cys142Ser and Cys145Thr mutants. Interestingly, neither cysteine mutation affects the structure of the adjacent Bbox2 domain when the two Bbox domains are engineered in their native tandem Bbox1-Bbox2 protein construct. Dynamic light scattering measurements suggest that the mutant Bbox1 domain has an increased propensity to form aggregates compared to the wild type Bbox1 domain. These studies provide insight into the mechanism by which mutations observed in XLOS affect the structure and function of the MID1 Bbox1 domain.
format	article
author	Katharine M Wright Kuanlin Wu Omotolani Babatunde Haijuan Du Michael A Massiah
author_facet	Katharine M Wright Kuanlin Wu Omotolani Babatunde Haijuan Du Michael A Massiah
author_sort	Katharine M Wright
title	XLOS-observed mutations of MID1 Bbox1 domain cause domain unfolding.
title_short	XLOS-observed mutations of MID1 Bbox1 domain cause domain unfolding.
title_full	XLOS-observed mutations of MID1 Bbox1 domain cause domain unfolding.
title_fullStr	XLOS-observed mutations of MID1 Bbox1 domain cause domain unfolding.
title_full_unstemmed	XLOS-observed mutations of MID1 Bbox1 domain cause domain unfolding.
title_sort	xlos-observed mutations of mid1 bbox1 domain cause domain unfolding.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/e2773c44394b438ab2c5905c4abf4f0b
work_keys_str_mv	AT katharinemwright xlosobservedmutationsofmid1bbox1domaincausedomainunfolding AT kuanlinwu xlosobservedmutationsofmid1bbox1domaincausedomainunfolding AT omotolanibabatunde xlosobservedmutationsofmid1bbox1domaincausedomainunfolding AT haijuandu xlosobservedmutationsofmid1bbox1domaincausedomainunfolding AT michaelamassiah xlosobservedmutationsofmid1bbox1domaincausedomainunfolding
_version_	1718414311503691776

XLOS-observed mutations of MID1 Bbox1 domain cause domain unfolding.

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