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

Mineyuki Mizuguchi (), Takayuki Obita, Tomohito Serita, Rieko Kojima, Yuko Nabeshima and Hitoshi Okazawa
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Mineyuki Mizuguchi: Faculty of Pharmaceutical Sciences, University of Toyama
Takayuki Obita: Faculty of Pharmaceutical Sciences, University of Toyama
Tomohito Serita: Faculty of Pharmaceutical Sciences, University of Toyama
Rieko Kojima: Faculty of Pharmaceutical Sciences, University of Toyama
Yuko Nabeshima: Faculty of Pharmaceutical Sciences, University of Toyama
Hitoshi Okazawa: Medical Research Institute, Tokyo Medical and Dental University; 1-5-45, Yushima, Bunkyo-ku

Nature Communications, 2014, vol. 5, issue 1, 1-8

Abstract: 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 U5–15kD. The U5–15kD 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.

Date: 2014
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DOI: 10.1038/ncomms4822

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