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dc.contributor.authorIbrahimi, O.A.
dc.contributor.authorZhang, F.
dc.contributor.authorEliseenkova, A.V.
dc.contributor.authorLinhardt, Robert J.
dc.contributor.authorMohammadi, M.
dc.date2004
dc.date.accessioned2022-06-27T16:16:41Z
dc.date.available2022-06-27T16:16:41Z
dc.date.issued2004
dc.identifier.citationProline to Arginine Mutations in FGF Receptors 1 and 3 Result in Pfeiffer and Muenke Craniosyntosis Syndromes Through the Enhancement of FGF Binding Affinity, O.A. Ibrahimi, F. Zhang, A. V. Eliseenkova, R. J. Linhardt, M. Mohammadi Human and Molecular Genetics, 13, 69-78, 2004.
dc.identifier.urihttps://doi.org/10.1093/hmg/ddh011
dc.identifier.urihttps://hdl.handle.net/20.500.13015/5797
dc.descriptionHuman and Molecular Genetics, 13, 69-78
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.abstractIdentical proline-->arginine gain-of-function mutations in fibroblast growth factor receptor (FGFR) 1 (Pro252Arg), FGFR2 (Pro253Arg) and FGFR3 (Pro250Arg), result in type I Pfeiffer, Apert and Muenke craniosynostosis syndromes, respectively. Here, we characterize the effects of proline-->arginine mutations in FGFR1c and FGFR3c on ligand binding using surface plasmon resonance and X-ray crystallography. Both Pro252Arg FGFR1c and Pro250Arg FGFR3c exhibit an enhancement in ligand binding in comparison to their respective wild-type receptors. Interestingly, binding of both mutant receptors to FGF9 was notably enhanced and implicates FGF9 as a potential pathophysiological ligand for mutant FGFRs in mediating craniosynostosis. The crystal structure, of Pro252Arg FGFR1c in complex with FGF2, demonstrates that the enhanced ligand binding is due to an additional set of receptor-ligand hydrogen bonds, similar to those gain-of-function interactions that occur in the Apert syndrome Pro253Arg FGFR2c-FGF2 crystal structure. However, unlike the Apert syndrome Pro253Arg FGFR2c mutant, neither the Pfeiffer syndrome Pro250Arg FGFR1c mutant nor the Muenke syndrome Pro250Arg FGFR3c mutant bound appreciably to FGF7 or FGF10. This observation provides a potential explanation for why the limb phenotypes, observed in type I Pfeiffer and Muenke syndromes, are less severe than the limb abnormalities observed in Apert syndrome. Hence, although analogous proline-->arginine mutations in FGFR1-3 act through a common structural mechanism to result in gain-of-function, differences in the primary sequence among FGFRs result in varying effects on ligand binding specificity.
dc.languageen_US
dc.language.isoENG
dc.relation.ispartofThe Linhardt Research Labs Online Collection
dc.relation.ispartofRensselaer Polytechnic Institute, Troy, NY
dc.relation.urihttps://harc.rpi.edu/
dc.subjectBiology
dc.subjectChemistry and chemical biology
dc.subjectChemical and biological engineering
dc.subjectBiomedical engineering
dc.titleProline to Arginine Mutations in FGF Receptors 1 and 3 Result in Pfeiffer and Muenke Craniosyntosis Syndromes Through the Enhancement of FGF Binding Affinity
dc.typeArticle
dcterms.isVersionOfhttps://doi.org/10.1093/hmg/ddh011
dc.rights.holderIn Copyright : this Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s). https://rightsstatements.org/page/InC/1.0/
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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