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Title: Changes in the folding landscape of the WW domain provide a molecular mechanism for an inherited genetic syndrome
Authors: Pucheta-Martinez, E
D'Amelio, N
Lelli, M
Martinez-Torrecuadrada, J.L
Sudol, M 
Saladino, G
Gervasio, F.L
Keywords: carrier protein
DNA binding protein
messenger RNA
nuclear protein
PQBP1 protein, human
protein binding
WBP11 protein, human
beta sheet
cerebral palsy
intellectual impairment
molecular dynamics
nuclear magnetic resonance
point mutation
protein folding
WW domain
X linked mental retardation
Carrier Proteins
Cerebral Palsy
DNA-Binding Proteins
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
Issue Date: 2016
Citation: Pucheta-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.
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 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.
Source Title: Scientific Reports
ISSN: 20452322
DOI: 10.1038/srep30293
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