title: Changes in the folding landscape of the WW domain provide a molecular mechanism for an inherited genetic syndrome.
abstract: WW 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 beta-strand-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.
authors.affiliation: Department of Chemistry, University College London, London WC1E 6BT, United Kingdom.
authors.forename: Encarna
authors.initials: E
authors.lastname: Pucheta-Martinez
authors.affiliation: Research Institute of Structural and Molecular Biology, University College London, London WC1E 6BT, United Kingdom.
authors.forename: Nicola
authors.initials: N
authors.lastname: D'Amelio
authors.affiliation: University of Florence, Department of Chemistry, Magnetic Resonance Center (CERM), 50019 Sesto Fiorentino (FI), Italy.
authors.forename: Moreno
authors.initials: M
authors.lastname: Lelli
authors.affiliation: Crystallography and Protein Engineering Unit, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernandez Almagro 3, 28029, Madrid, Spain.
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Martinez-Torrecuadrada
authors.affiliation: Institute of Molecular and Cell Biology A*STAR, 61 Biopolis, Singapore 138673, Republic of Singapore.|Mechanobiology Institute, 5A Engineering Drive 1, Singapore 117411, Republic of Singapore.|National University of Singapore, Department of Physiology, The Yong Loo Li School of Medicine, 2 Medical Drive, Singapore 117597, Republic of Singapore.
authors.forename: Marius
authors.initials: M
authors.lastname: Sudol
authors.affiliation: Department of Chemistry, University College London, London WC1E 6BT, United Kingdom.|Research Institute of Structural and Molecular Biology, University College London, London WC1E 6BT, United Kingdom.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Saladino
authors.affiliation: Department of Chemistry, University College London, London WC1E 6BT, United Kingdom.|Research Institute of Structural and Molecular Biology, University College London, London WC1E 6BT, United Kingdom.
authors.forename: Francesco Luigi
authors.initials: FL
authors.lastname: Gervasio
mesh_terms: D002352:Carrier Proteins / Q000235:genetics*; D002547:Cerebral Palsy / Q000235:genetics* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D038901:X-Linked Intellectual Disability / Q000235:genetics* / Q000473:pathology; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics; D011485:Protein Binding; D000072757:Protein Conformation, beta-Strand; D017510:Protein Folding; D000072260:RNA Splicing Factors; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D000074585:WW Domains / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C119246:PQBP1 protein, human; D000072260:RNA Splicing Factors; D012333:RNA, Messenger; C434066:WBP11 protein, human