Symmetry breaking during homodimeric assembly activates an E3 ubiquitin ligase

Abstract C-terminus of Hsc/p70-Interacting Protein (CHIP) is a homodimeric E3 ubiquitin ligase. Each CHIP monomer consists of a tetratricopeptide-repeat (TPR), helix-turn-helix (HH), and U-box domain. In contrast to nearly all homodimeric proteins, CHIP is asymmetric. To uncover the origins of asymm...

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Autores principales:	Zhaofeng Ye, Patrick G. Needham, Samuel K. Estabrooks, Susan K. Whitaker, Brandon L. Garcia, Saurav Misra, Jeffrey L. Brodsky, Carlos J. Camacho
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b2c7a5756fd942c79d8b34c96e08a1e3
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spelling	oai:doaj.org-article:b2c7a5756fd942c79d8b34c96e08a1e32021-12-02T12:32:54ZSymmetry breaking during homodimeric assembly activates an E3 ubiquitin ligase10.1038/s41598-017-01880-42045-2322https://doaj.org/article/b2c7a5756fd942c79d8b34c96e08a1e32017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01880-4https://doaj.org/toc/2045-2322Abstract C-terminus of Hsc/p70-Interacting Protein (CHIP) is a homodimeric E3 ubiquitin ligase. Each CHIP monomer consists of a tetratricopeptide-repeat (TPR), helix-turn-helix (HH), and U-box domain. In contrast to nearly all homodimeric proteins, CHIP is asymmetric. To uncover the origins of asymmetry, we performed molecular dynamics simulations of dimer assembly. We determined that a CHIP monomer is most stable when the HH domain has an extended helix that supports intra-monomer TPR-U-box interaction, blocking the E2-binding surface of the U-box. We also discovered that monomers first dimerize symmetrically through their HH domains, which then triggers U-box dimerization. This brings the extended helices into close proximity, including a repulsive stretch of positively charged residues. Unable to smoothly unwind, this conflict bends the helices until the helix of one protomer breaks to relieve the repulsion. The abrupt snapping of the helix forces the C-terminal residues of the other protomer to disrupt that protomer’s TPR-U-box tight binding interface, swiftly exposing and activating one of the E2 binding sites. Mutagenesis and biochemical experiments confirm that C-terminal residues are necessary both to maintain CHIP stability and function. This novel mechanism indicates how a ubiquitin ligase maintains an inactive monomeric form that rapidly activates only after asymmetric assembly.Zhaofeng YePatrick G. NeedhamSamuel K. EstabrooksSusan K. WhitakerBrandon L. GarciaSaurav MisraJeffrey L. BrodskyCarlos J. CamachoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-9 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Zhaofeng Ye Patrick G. Needham Samuel K. Estabrooks Susan K. Whitaker Brandon L. Garcia Saurav Misra Jeffrey L. Brodsky Carlos J. Camacho Symmetry breaking during homodimeric assembly activates an E3 ubiquitin ligase
description	Abstract C-terminus of Hsc/p70-Interacting Protein (CHIP) is a homodimeric E3 ubiquitin ligase. Each CHIP monomer consists of a tetratricopeptide-repeat (TPR), helix-turn-helix (HH), and U-box domain. In contrast to nearly all homodimeric proteins, CHIP is asymmetric. To uncover the origins of asymmetry, we performed molecular dynamics simulations of dimer assembly. We determined that a CHIP monomer is most stable when the HH domain has an extended helix that supports intra-monomer TPR-U-box interaction, blocking the E2-binding surface of the U-box. We also discovered that monomers first dimerize symmetrically through their HH domains, which then triggers U-box dimerization. This brings the extended helices into close proximity, including a repulsive stretch of positively charged residues. Unable to smoothly unwind, this conflict bends the helices until the helix of one protomer breaks to relieve the repulsion. The abrupt snapping of the helix forces the C-terminal residues of the other protomer to disrupt that protomer’s TPR-U-box tight binding interface, swiftly exposing and activating one of the E2 binding sites. Mutagenesis and biochemical experiments confirm that C-terminal residues are necessary both to maintain CHIP stability and function. This novel mechanism indicates how a ubiquitin ligase maintains an inactive monomeric form that rapidly activates only after asymmetric assembly.
format	article
author	Zhaofeng Ye Patrick G. Needham Samuel K. Estabrooks Susan K. Whitaker Brandon L. Garcia Saurav Misra Jeffrey L. Brodsky Carlos J. Camacho
author_facet	Zhaofeng Ye Patrick G. Needham Samuel K. Estabrooks Susan K. Whitaker Brandon L. Garcia Saurav Misra Jeffrey L. Brodsky Carlos J. Camacho
author_sort	Zhaofeng Ye
title	Symmetry breaking during homodimeric assembly activates an E3 ubiquitin ligase
title_short	Symmetry breaking during homodimeric assembly activates an E3 ubiquitin ligase
title_full	Symmetry breaking during homodimeric assembly activates an E3 ubiquitin ligase
title_fullStr	Symmetry breaking during homodimeric assembly activates an E3 ubiquitin ligase
title_full_unstemmed	Symmetry breaking during homodimeric assembly activates an E3 ubiquitin ligase
title_sort	symmetry breaking during homodimeric assembly activates an e3 ubiquitin ligase
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/b2c7a5756fd942c79d8b34c96e08a1e3
work_keys_str_mv	AT zhaofengye symmetrybreakingduringhomodimericassemblyactivatesane3ubiquitinligase AT patrickgneedham symmetrybreakingduringhomodimericassemblyactivatesane3ubiquitinligase AT samuelkestabrooks symmetrybreakingduringhomodimericassemblyactivatesane3ubiquitinligase AT susankwhitaker symmetrybreakingduringhomodimericassemblyactivatesane3ubiquitinligase AT brandonlgarcia symmetrybreakingduringhomodimericassemblyactivatesane3ubiquitinligase AT sauravmisra symmetrybreakingduringhomodimericassemblyactivatesane3ubiquitinligase AT jeffreylbrodsky symmetrybreakingduringhomodimericassemblyactivatesane3ubiquitinligase AT carlosjcamacho symmetrybreakingduringhomodimericassemblyactivatesane3ubiquitinligase
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Symmetry breaking during homodimeric assembly activates an E3 ubiquitin ligase

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