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dc.rights.licenseOpen Access
dc.rights.licenseA full text version is available in DSpace@RPI
dc.contributor.authorZhao, J.
dc.contributor.authorLiu, X.
dc.contributor.authorBlayney, A.
dc.contributor.authorZhang, Y.
dc.contributor.authorGandy, L.
dc.contributor.authorMirsky, P.O.
dc.contributor.authorSmith, N.
dc.contributor.authorZhang, F.
dc.contributor.authorLinhardt, Robert J.
dc.contributor.authorChen, J.
dc.contributor.authorBaines, C.
dc.contributor.authorLoh, S.N.
dc.contributor.authorWang, C.
dc.date2022
dc.date.accessioned2022-06-23T01:46:38Z
dc.date.available2022-06-23T01:46:38Z
dc.date.issued2022
dc.identifier.citationIntrinsically disordered N-terminal domain (NTD) of p53 interacts with mitochondrial PTP regulator Cyclophilin D, J. Zhao, X. Liu, A. Blayney, Y. Zhang, L. Gandy, P. O. Mirsky, N. Smith, F. Zhang, R. J. Linhardt, J. Chen, C. Baines, S. N. Loh, C. Wang, Journal of Molecular Biology, 434, 167552, 2022.
dc.identifier.urihttps://doi.org/10.1016/j.jmb.2022.167552
dc.descriptionJournal of Molecular Biology, 434, 167552
dc.descriptionNote : if this item contains full text it may be a preprint, author manuscript, or a Gold OA copy that permits redistribution with a license such as CC BY. The final version is available through the publisher’s platform.
dc.description.abstractMitochondrial permeability transition pore (mPTP) plays crucial roles in cell death in a variety of diseases, including ischemia/reperfusion injury in heart attack and stroke, neurodegenerative conditions, and cancer. To date, cyclophilin D is the only confirmed component of mPTP. Under stress, p53 can translocate into mitochondria and interact with CypD, triggering necrosis and cell growth arrest. However, the molecular details of p53/CypD interaction are still poorly understood. Previously, several studies reported that p53 interacts with CypD through its DNA-binding domain (DBD). However, using surface plasmon resonance (SPR), we found that both NTD-DBD, NTD and NTD (1-70) bind to CypD at ∼μM KD. In solution NMR, NTD binds CypD with μM affinity and mimics the pattern of FLp53 binding in chemical shift perturbation. In contrast, neither solution NMR nor fluorescence anisotropy detected DBD binding to CypD. Thus, instead of DBD, NTD is the major CypD binding site on p53. NMR titration and MD simulation revealed that NTD binds CypD with broad and dynamic interfaces dominated by electrostatic interactions. NTD 20-70 was further identified as the minimal binding region for CypD interaction, and two NTD fragments, D1 (residues 22-44) and D2 (58-70), can each bind CypD with mM affinity. Our detailed biophysical characterization of the dynamic interface between NTD and CypD provides novel insights on the p53-dependent mPTP opening and drug discovery targeting NTD/CypD interface in diseases.
dc.languageENG
dc.language.isoen_US
dc.publisherElsevier
dc.relation.ispartofThe Linhardt Research Labs Online Collection
dc.relation.ispartofRensselaer Polytechnic Institute, Troy, NY
dc.relation.urihttps://harc.rpi.edu/
dc.rightsAttribution-NonCommercial-NoDerivs 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/us/*
dc.subjectBiology
dc.subjectChemistry and chemical biology
dc.subjectChemical and biological engineering
dc.subjectBiomedical engineering
dc.titleIntrinsically disordered N-terminal domain (NTD) of p53 interacts with mitochondrial PTP regulator Cyclophilin D
dc.typeArticle
dcterms.accessRightsA full text version is available in DSpace@RPI
dcterms.isVersionOfhttps://doi.org/10.1016/j.jmb.2022.167552
dc.rights.holderCC BY-NC-ND : this license allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
dc.creator.identifierhttps://orcid.org/0000-0003-2219-5833
dc.relation.departmentThe Linhardt Research Labs.
dc.relation.departmentThe Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies (CBIS)


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