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dc.creatorXia, J
dc.creatorLevy, RM
dc.date.accessioned2021-02-03T19:01:02Z
dc.date.available2021-02-03T19:01:02Z
dc.date.issued2014-05-01
dc.identifier.issn1520-6106
dc.identifier.issn1520-5207
dc.identifier.doihttp://dx.doi.org/10.34944/dspace/5866
dc.identifier.other24702481 (pubmed)
dc.identifier.urihttp://hdl.handle.net/20.500.12613/5884
dc.description.abstractThe Crk adaptor proteins play a central role as a molecular timer for the formation of protein complexes including various growth and differentiation factors. The loss of regulation of Crk results in many kinds of cancers. A self-regulatory mechanism for Crk was recently proposed, which involves domain-domain rearrangement. It is initiated by a cis-trans isomerization of a specific proline residue (Pro238 in chicken Crk II) and can be accelerated by Cyclophilin A. To understand how the proline switch controls the autoinhibition at the molecular level, we performed large-scale molecular dynamics and metadynamics simulations in the context of short peptides and multidomain constructs of chicken Crk II. We found that the equilibrium and kinetic properties of the macrostates are regulated not only by the local environments of specified prolines but also by the global organization of multiple domains. We observe the two macrostates (cis closed/autoinhibited and trans open/uninhibited) consistent with NMR experiments and predict barriers. We also propose an intermediate state, the trans closed state, which interestingly was reported to be a prevalent state in human Crk II. The existence of this macrostate suggests that the rate of switching off the autoinhibition by Cyp A may be limited by the relaxation rate of this intermediate state. © 2014 American Chemical Society.
dc.format.extent4535-4545
dc.language.isoen
dc.relation.haspartJournal of Physical Chemistry B
dc.relation.isreferencedbyAmerican Chemical Society (ACS)
dc.subjectCyclophilin A
dc.subjectHumans
dc.subjectHydrophobic and Hydrophilic Interactions
dc.subjectKinetics
dc.subjectMolecular Dynamics Simulation
dc.subjectProline
dc.subjectProtein Stability
dc.subjectProto-Oncogene Proteins c-crk
dc.subjectSignal Transduction
dc.subjectThermodynamics
dc.subjectsrc Homology Domains
dc.titleMolecular dynamics of the proline switch and its role in Crk signaling
dc.typeArticle
dc.type.genreJournal Article
dc.relation.doi10.1021/jp5013297
dc.ada.noteFor Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu
dc.creator.orcidXia, Junchao|0000-0002-5026-2872
dc.date.updated2021-02-03T19:00:58Z
refterms.dateFOA2021-02-03T19:01:03Z


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