2026-06-14T03:42:14Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/85562024-11-29T13:42:22Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Pucheta-Martinez, Encarna author D'Amelio, Nicola author Lelli, Moreno author Martinez Torrecuadrada, Jorge Luis author Sudol, Marius author Saladino, Giorgio author Gervasio, Francesco Luigi author 2016-07-26 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. Sci Rep. 2016 ;6:30293. 10.1038/srep30293 2045-2322 2045-2322 Scientific reports 27456546 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