Symmetry breaking during homodimeric assembly activates an E3 ubiquitin ligase

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dc.contributor.author Ye, Z.
dc.contributor.author Needham, P. G.
dc.contributor.author Estabrooks, S. K.
dc.contributor.author Whitaker, Susan K.
dc.contributor.author Garcia, Brandon L.
dc.contributor.author Misra, Saurav
dc.contributor.author Brodsky, J. L.
dc.contributor.author Camacho, C. J.
dc.date.accessioned 2017-11-30T21:40:52Z
dc.date.available 2017-11-30T21:40:52Z
dc.identifier.uri http://hdl.handle.net/2097/38327
dc.description Citation: Ye, Z., Needham, P. G., Estabrooks, S. K., Whitaker, S. K., Garcia, B. L., Misra, S., . . . Camacho, C. J. (2017). Symmetry breaking during homodimeric assembly activates an E3 ubiquitin ligase. Scientific Reports, 7(1). doi:10.1038/s41598-017-01880-4
dc.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. © 2017 The Author(s).
dc.relation.uri https://doi.org/10.1038/s41598-017-01880-4
dc.rights Attribution 4.0 International (CC BY 4.0)
dc.rights.uri https://creativecommons.org/licenses/by/4.0/
dc.title Symmetry breaking during homodimeric assembly activates an E3 ubiquitin ligase
dc.date.published 2017
dc.citation.doi 10.1038/s41598-017-01880-4
dc.citation.issn 2045-2322
dc.citation.issue 1
dc.citation.jtitle Scientific Reports
dc.citation.volume 7
dc.contributor.authoreid misras
dc.contributor.authoreid garciab
dc.contributor.kstate Misra, Saurav
dc.contributor.kstate Garcia, Brandon L.


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