Y65C missense mutation in the WW domain of the Golabi-Ito-Hall syndrome protein PQBP1 affects its binding activity and deregulates pre-mRNA splicing.
The PQBP1 (polyglutamine tract-binding protein 1) gene encodes a nuclear protein that regulates pre-mRNA splicing and transcription. Mutations in the PQBP1 gene were reported in several X chromosome-linked mental retardation disorders including Golabi-Ito-Hall syndrome. The missense mutation that causes this syndrome is unique among other PQBP1 mutations reported to date because it maps within a functional domain of PQBP1, known as the WW domain. The mutation substitutes tyrosine 65 with cysteine and is located within the conserved core of aromatic amino acids of the domain. We show here that the binding property of the Y65C-mutated WW domain and the full-length mutant protein toward its cognate proline-rich ligands was diminished. Furthermore, in Golabi-Ito-Hall-derived lymphoblasts we showed that the complex between PQBP1-Y65C and WBP11 (WW domain-binding protein 11) splicing factor was compromised. In these cells a substantial decrease in pre-mRNA splicing efficiency was detected. Our study points to the critical role of the WW domain in the function of the PQBP1 protein and provides an insight into the molecular mechanism that underlies the X chromosome-linked mental retardation entities classified globally as Renpenning syndrome.
Tapia
Victor E
VE
Institut für Medizinische Immunologie, Charité-Universitätsmedizin Berlin, Berlin 10115, Germany.
Nicolaescu
Emilia
E
McDonald
Caleb B
CB
Musi
Valeria
V
Oka
Tsutomu
T
Inayoshi
Yujin
Y
Satteson
Adam C
AC
Mazack
Virginia
V
Humbert
Jasper
J
Gaffney
Christian J
CJ
Beullens
Monique
M
Schwartz
Charles E
CE
Landgraf
Christiane
C
Volkmer
Rudolf
R
Pastore
Annalisa
A
Farooq
Amjad
A
Bollen
Mathieu
M
Sudol
Marius
M
D017398:Alternative Splicing; D002151:Calorimetry / Q000379:methods; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics*; D002942:Circular Dichroism; D004268:DNA-Binding Proteins; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008024:Ligands; D008214:Lymphocytes / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D009154:Mutation; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics*; D011392:Proline / Q000737:chemistry; D017434:Protein Structure, Tertiary; D020349:Surface Plasmon Resonance; D014158:Transcription, Genetic
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D008024:Ligands; D009687:Nuclear Proteins; C119246:PQBP1 protein, human; D011392:Proline
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