Mutations in the PQBP1 gene prevent its interaction with the spliceosomal protein U5-15 kD

Nat Commun. 2014 Apr 30:5:3822. doi: 10.1038/ncomms4822.

Abstract

A loss-of-function of polyglutamine tract-binding protein 1 (PQBP1) induced by frameshift mutations is believed to cause X-linked mental retardation. However, the mechanism by which structural changes in PQBP1 lead to mental retardation is unknown. Here we present the crystal structure of a C-terminal fragment of PQBP1 in complex with the spliceosomal protein U5-15 kD. The U5-15 kD hydrophobic groove recognizes a YxxPxxVL motif in PQBP1, and mutations within this motif cause a loss-of-function phenotype of PQBP1 in vitro. The YxxPxxVL motif is absent in all PQBP1 frameshift mutants seen in cases of mental retardation. These results suggest a mechanism by which the loss of the YxxPxxVL motif could lead to the functional defects seen in this type of mental retardation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / chemistry*
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism*
  • Chromatography, Gel
  • Crystallization
  • DNA-Binding Proteins
  • Fluorescence
  • Humans
  • Magnetic Resonance Spectroscopy
  • Models, Molecular*
  • Mutation / genetics*
  • Nuclear Proteins / chemistry*
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism*
  • Protein Conformation
  • Ribonucleoprotein, U5 Small Nuclear / metabolism*
  • Spliceosomes / metabolism*

Substances

  • Carrier Proteins
  • DNA-Binding Proteins
  • Nuclear Proteins
  • PQBP1 protein, human
  • Ribonucleoprotein, U5 Small Nuclear
  • TXNL4A protein, human

Associated data

  • PDB/4BWQ
  • PDB/4BWS
  • PDB/4CDO