Please use this identifier to cite or link to this item: https://doi.org/10.1038/srep30293
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
chemistry
genetics
human
intellectual impairment
molecular dynamics
nuclear magnetic resonance
pathology
point mutation
protein folding
WW domain
X linked mental retardation
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
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. https://doi.org/10.1038/srep30293
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
URI: https://scholarbank.nus.edu.sg/handle/10635/174000
ISSN: 20452322
DOI: 10.1038/srep30293
Appears in Collections:Elements
Staff Publications

Show full item record
Files in This Item:
File Description SizeFormatAccess SettingsVersion 
10_1038_srep30293.pdf2.54 MBAdobe PDF

OPEN

NoneView/Download

SCOPUSTM   
Citations

5
checked on Jan 12, 2021

Page view(s)

37
checked on Jan 15, 2021

Google ScholarTM

Check

Altmetric


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.