Y65C missense mutation in the WW domain of the Golabi-Ito-Hall syndrome protein PQBP1 affects its binding activity and deregulates pre-mRNA splicing

Victor E. Tapia, Emilia Nicolaescu, Caleb B. McDonald, Valeria Musi, Tsutomu Oka, Yujin Inayoshi, Adam C. Satteson, Virginia Mazack, Jasper Humbert, Christian J. Gaffney, Monique Beullens, Charles E. Schwartz, Christiane Landgraf, Rudolf Volkmer, Annalisa Pastore, Amjad Farooq, Mathieu Bollen, Marius Sudol

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)19391-19401
Number of pages11
JournalJournal of Biological Chemistry
Volume285
Issue number25
DOIs
StatePublished - Jun 18 2010

Fingerprint

RNA Precursors
Missense Mutation
Chromosomes
X-Linked Mental Retardation
Carrier Proteins
Genes
X Chromosome
Aromatic Amino Acids
Mutation
Mutant Proteins
Transcription
Nuclear Proteins
Proline
Protein Splicing
Cysteine
Tyrosine
Proteins
Ligands
Renpenning syndrome 1
polyglutamine

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Y65C missense mutation in the WW domain of the Golabi-Ito-Hall syndrome protein PQBP1 affects its binding activity and deregulates pre-mRNA splicing. / Tapia, Victor E.; Nicolaescu, Emilia; McDonald, Caleb B.; Musi, Valeria; Oka, Tsutomu; Inayoshi, Yujin; Satteson, Adam C.; Mazack, Virginia; Humbert, Jasper; Gaffney, Christian J.; Beullens, Monique; Schwartz, Charles E.; Landgraf, Christiane; Volkmer, Rudolf; Pastore, Annalisa; Farooq, Amjad; Bollen, Mathieu; Sudol, Marius.

In: Journal of Biological Chemistry, Vol. 285, No. 25, 18.06.2010, p. 19391-19401.

Research output: Contribution to journalArticle

Tapia, VE, Nicolaescu, E, McDonald, CB, Musi, V, Oka, T, Inayoshi, Y, Satteson, AC, Mazack, V, Humbert, J, Gaffney, CJ, Beullens, M, Schwartz, CE, Landgraf, C, Volkmer, R, Pastore, A, Farooq, A, Bollen, M & Sudol, M 2010, 'Y65C missense mutation in the WW domain of the Golabi-Ito-Hall syndrome protein PQBP1 affects its binding activity and deregulates pre-mRNA splicing', Journal of Biological Chemistry, vol. 285, no. 25, pp. 19391-19401. https://doi.org/10.1074/jbc.M109.084525
Tapia, Victor E. ; Nicolaescu, Emilia ; McDonald, Caleb B. ; Musi, Valeria ; Oka, Tsutomu ; Inayoshi, Yujin ; Satteson, Adam C. ; Mazack, Virginia ; Humbert, Jasper ; Gaffney, Christian J. ; Beullens, Monique ; Schwartz, Charles E. ; Landgraf, Christiane ; Volkmer, Rudolf ; Pastore, Annalisa ; Farooq, Amjad ; Bollen, Mathieu ; Sudol, Marius. / Y65C missense mutation in the WW domain of the Golabi-Ito-Hall syndrome protein PQBP1 affects its binding activity and deregulates pre-mRNA splicing. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 25. pp. 19391-19401.
@article{222d0db090ba45bf911dff24db4eb51e,
title = "Y65C missense mutation in the WW domain of the Golabi-Ito-Hall syndrome protein PQBP1 affects its binding activity and deregulates pre-mRNA splicing",
abstract = "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.",
author = "Tapia, {Victor E.} and Emilia Nicolaescu and McDonald, {Caleb B.} and Valeria Musi and Tsutomu Oka and Yujin Inayoshi and Satteson, {Adam C.} and Virginia Mazack and Jasper Humbert and Gaffney, {Christian J.} and Monique Beullens and Schwartz, {Charles E.} and Christiane Landgraf and Rudolf Volkmer and Annalisa Pastore and Amjad Farooq and Mathieu Bollen and Marius Sudol",
year = "2010",
month = "6",
day = "18",
doi = "10.1074/jbc.M109.084525",
language = "English",
volume = "285",
pages = "19391--19401",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "25",

}

TY - JOUR

T1 - Y65C missense mutation in the WW domain of the Golabi-Ito-Hall syndrome protein PQBP1 affects its binding activity and deregulates pre-mRNA splicing

AU - Tapia, Victor E.

AU - Nicolaescu, Emilia

AU - McDonald, Caleb B.

AU - Musi, Valeria

AU - Oka, Tsutomu

AU - Inayoshi, Yujin

AU - Satteson, Adam C.

AU - Mazack, Virginia

AU - Humbert, Jasper

AU - Gaffney, Christian J.

AU - Beullens, Monique

AU - Schwartz, Charles E.

AU - Landgraf, Christiane

AU - Volkmer, Rudolf

AU - Pastore, Annalisa

AU - Farooq, Amjad

AU - Bollen, Mathieu

AU - Sudol, Marius

PY - 2010/6/18

Y1 - 2010/6/18

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=77953500547&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77953500547&partnerID=8YFLogxK

U2 - 10.1074/jbc.M109.084525

DO - 10.1074/jbc.M109.084525

M3 - Article

C2 - 20410308

AN - SCOPUS:77953500547

VL - 285

SP - 19391

EP - 19401

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 25

ER -