Please use this identifier to cite or link to this item: https://doi.org/10.1038/srep30293
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dc.titleChanges in the folding landscape of the WW domain provide a molecular mechanism for an inherited genetic syndrome
dc.contributor.authorPucheta-Martinez, E
dc.contributor.authorD'Amelio, N
dc.contributor.authorLelli, M
dc.contributor.authorMartinez-Torrecuadrada, J.L
dc.contributor.authorSudol, M
dc.contributor.authorSaladino, G
dc.contributor.authorGervasio, F.L
dc.date.accessioned2020-09-02T06:52:11Z
dc.date.available2020-09-02T06:52:11Z
dc.date.issued2016
dc.identifier.citationPucheta-Martinez, E, D'Amelio, N, Lelli, M, Martinez-Torrecuadrada, J.L, Sudol, M, Saladino, G, Gervasio, F.L (2016). Changes in the folding landscape of the WW domain provide a molecular mechanism for an inherited genetic syndrome. Scientific Reports 6 : 30293. ScholarBank@NUS Repository. https://doi.org/10.1038/srep30293
dc.identifier.issn20452322
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/174000
dc.description.abstractWW domains are small domains present in many human proteins with a wide array of functions and acting through the recognition of proline-rich sequences. The WW domain belonging to polyglutamine tract-binding protein 1 (PQBP1) is of particular interest due to its direct involvement in several X chromosome-linked intellectual disabilities, including Golabi-Ito-Hall (GIH) syndrome, where a single point mutation (Y65C) correlates with the development of the disease. The mutant cannot bind to its natural ligand WBP11, which regulates mRNA processing. In this work we use high-field high-resolution NMR and enhanced sampling molecular dynamics simulations to gain insight into the molecular causes the disease. We find that the wild type protein is partially unfolded exchanging among multiple betastrand-like conformations in solution. The Y65C mutation further destabilizes the residual fold and primes the protein for the formation of a disulphide bridge, which could be at the origin of the loss of function.
dc.sourceUnpaywall 20200831
dc.subjectcarrier protein
dc.subjectDNA binding protein
dc.subjectmessenger RNA
dc.subjectnuclear protein
dc.subjectPQBP1 protein, human
dc.subjectprotein binding
dc.subjectWBP11 protein, human
dc.subjectbeta sheet
dc.subjectcerebral palsy
dc.subjectchemistry
dc.subjectgenetics
dc.subjecthuman
dc.subjectintellectual impairment
dc.subjectmolecular dynamics
dc.subjectnuclear magnetic resonance
dc.subjectpathology
dc.subjectpoint mutation
dc.subjectprotein folding
dc.subjectWW domain
dc.subjectX linked mental retardation
dc.subjectCarrier Proteins
dc.subjectCerebral Palsy
dc.subjectDNA-Binding Proteins
dc.subjectHumans
dc.subjectIntellectual Disability
dc.subjectMental Retardation, X-Linked
dc.subjectMolecular Dynamics Simulation
dc.subjectNuclear Magnetic Resonance, Biomolecular
dc.subjectNuclear Proteins
dc.subjectPoint Mutation
dc.subjectProtein Binding
dc.subjectProtein Conformation, beta-Strand
dc.subjectProtein Folding
dc.subjectRNA, Messenger
dc.subjectWW Domains
dc.typeArticle
dc.contributor.departmentDEPT OF PHYSIOLOGY
dc.description.doi10.1038/srep30293
dc.description.sourcetitleScientific Reports
dc.description.volume6
dc.description.page30293
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