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

• DOI: 10.1038/ncomms4822
• Publication Date: 2014-04-30T10:41:41Z
• Authors: Mineyuki Mizuguchi; Takayuki Obita; Tomohito Serita; Rieko Kojima; Yuko Nabeshima; Hitoshi Okazawa
• Keywords: Models, Molecular; 0301 basic medicine; Magnetic Resonance Spectroscopy; Protein Conformation; Nuclear Proteins; Fluorescence; DNA-Binding Proteins; 03 medical and health sciences; Mutation; Chromatography, Gel; Spliceosomes; Humans; Carrier Proteins; Crystallization; Ribonucleoprotein, U5 Small Nuclear

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.