Mutations in the PQBP1 gene prevent its interaction with the spliceosomal protein U5-15 kD.
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.
1] Faculty of Pharmaceutical Sciences, University of Toyama; 2630, Sugitani, Toyama 930-0194, Japan [2] Graduate School of Innovative Life Science, University of Toyama; 2630, Sugitani, Toyama 930-0194, Japan [3].
Mineyuki
M
Mizuguchi
1] Faculty of Pharmaceutical Sciences, University of Toyama; 2630, Sugitani, Toyama 930-0194, Japan [2].
Takayuki
T
Obita
Faculty of Pharmaceutical Sciences, University of Toyama; 2630, Sugitani, Toyama 930-0194, Japan.
Tomohito
T
Serita
1] Faculty of Pharmaceutical Sciences, University of Toyama; 2630, Sugitani, Toyama 930-0194, Japan [2].
Rieko
R
Kojima
1] Faculty of Pharmaceutical Sciences, University of Toyama; 2630, Sugitani, Toyama 930-0194, Japan [2] Graduate School of Innovative Life Science, University of Toyama; 2630, Sugitani, Toyama 930-0194, Japan.
Yuko
Y
Nabeshima
1] Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University; 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan [2] Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Hitoshi
H
Okazawa
D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism*; D002850:Chromatography, Gel; D003460:Crystallization; D004268:DNA-Binding Proteins; D005453:Fluorescence; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism*; D011487:Protein Conformation; D017415:Ribonucleoprotein, U5 Small Nuclear / Q000378:metabolism*; D017381:Spliceosomes / Q000378:metabolism*
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C119246:PQBP1 protein, human; D017415:Ribonucleoprotein, U5 Small Nuclear; C506012:TXNL4A protein, human