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.
Highlights
Deviations of opposite sign are displayed in yellow
The 1H,15N HSQC spectrum of the PQBP1 WW domain (Fig. 1A), reveals that the protein exchanges among multiple conformations in solution, a behavior which has been reported for a few other WW domains[19,21,32]
Conformational exchange between open and closed forms have been reported for other WW domains[19,21,32]
Summary
Deviations of opposite sign are displayed in yellow. Residues for which data are not available (unassigned) are colored in gray. The structure has been studied in the presence of a binding peptide which might stabilize the fold[17,19,28,30,31,32]. The X-ray structure of the C-terminus of PQBP1 has been determined in complex with spliceosomal protein U5-15kD35, showing how a YxxPxxVL motif in PQBP1 is recognized. We investigate the underlying causes of the GIH disease by using a combination of high-field solution NMR and state-of-the-art enhanced sampling simulations to determine the effect of the Y65C mutation on the structure and dynamics of the WW domain of PQBP1
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