Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/8556
Changes in the folding landscape of the WW domain provide a molecular mechanism for an inherited genetic syndrome
Sci Rep. 2016 ;6:30293.
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.
Carrier Proteins | Cerebral Palsy | DNA-Binding Proteins | Humans | Intellectual Disability | Mental Retardation, X-Linked | Molecular Dynamics Simulation | Nuclear Magnetic Resonance, Biomolecular | Nuclear Proteins | Point Mutation | Protein Binding | Protein Conformation, beta-Strand | Protein Folding | RNA, Messenger | WW Domains
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