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

Mizuguchi, Mineyuki; Obita, Takayuki; Serita, T.; Kojima, Ryosuke; Nabeshima, Yuko; Okazawa, Hitoshi

doi:10.1038/ncomms4822

Cited by 33 publications

(44 citation statements)

References 41 publications

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“…A). U5‐15kD binds to the immobilized PQBP1(223–265) with a K D value of 33.6 ± 2.6 μ m , which is similar to the K D value between PQBP1(223–265) and the immobilized U5‐15kD in our previous study (19.7 ± 3.4 μ m ) . We also performed the same experiment using the immobilized PQBP1(193–265).…”

Section: Resultssupporting

confidence: 80%

“…A,B). The Val81 and Ile90 are located near the PQBP1‐binding groove of U5‐15kD . On the other hand, the resonances of Val81 and Ile90 were partially recovered by adding the excess amount of LD‐WBP11(455–469) (Fig.…”

Section: Resultsmentioning

confidence: 96%

“…NH 4 Cl and13 C-glucose. The NMR sample was prepared by adding 25 lL of D 2 O to 500 lL of the protein solution containing 100 lM 13 C/ 15 N-labeled U5-15kD, 80 lM full-length PQBP1, 430 lM LD-WBP11(455-469), 20 mM sodium phosphate (pH 7.5), 50 mM NaCl, and 1 mM dithiothreitol.…”

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confidence: 99%

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Allosteric modulation of the binding affinity between PQBP1 and the spliceosomal protein U5‐15kD

et al. 2016

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Edited by Michael IbbaPolyglutamine tract-binding protein 1 (PQBP1) is an intrinsically disordered protein composed of a small folded WW domain and a long disordered region. PQBP1 binds to spliceosomal proteins WBP11 and U5-15kD through its N-terminal WW domain and C-terminal region, respectively. Here, we reveal that the binding between PQBP1 and WBP11 reduces the binding affinity between PQBP1 and U5-15kD. Our results suggest that the interaction between PQBP1 and WBP11 negatively modulates the U5-15kD binding of PQBP1 by an allosteric mechanism.

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Section: Resultssupporting

confidence: 80%

Section: Resultsmentioning

confidence: 96%

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Allosteric modulation of the binding affinity between PQBP1 and the spliceosomal protein U5‐15kD

et al. 2016

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“…Aberrant splicing, which is involved in several neurological human diseases [Feng and Xie, ], could be a putative pathomechanism. It is possible that CWF19L1 is in a line with other genes for neurological diseases involved in basic cellular processes such as mRNA splicing [Kalscheuer et al, ; Feng and Xie, ; Mizuguchi et al, ].…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing reveals a novel CWF19L1 mutation associated with intellectual disability and cerebellar atrophy

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et al. 2016

American J of Med Genetics Pt A

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Intellectual disability (ID) with cerebellar ataxia comprises a genetically heterogeneous group of neurodevelopmental disorders. We identified a homozygous frameshift mutation in CWF19L1 (c.467delC; p.(P156Hfs*33)) by a combination of linkage analysis and Whole Exome Sequencing in a consanguineous Turkish family with a 9-year-old boy affected by early onset cerebellar ataxia and mild ID. Serial MRI showed mildly progressive cerebellar atrophy. Absent C19L1 protein expression in lymphoblastoid cell lines strongly suggested that c.467delC is a disease-causing alteration. One further pregnancy of the mother had been terminated at 22 weeks of gestation because of a small cerebellum and agenesis of corpus callosum. The homozygous CWF19L1 variant was also present in the fetus. Postmortem examination of the fetus in addition showed unilateral hexadactyly and vertebral malformations. These features have not been reported and may represent an expansion of the CWF19L1-related phenotypic spectrum, but could also be due to another, possibly autosomal recessive disorder. The exact function of the evolutionarily highly conserved C19L1 protein is unknown. So far, homozygous or compound heterozygous mutations in CWF19L1 have been identified in two Turkish siblings and a Dutch girl, respectively, affected by cerebellar ataxia and ID. A zebrafish model showed that CWF19L1 loss-of-function mutations result in abnormal cerebellar morphology and movement disorders. Our report corroborates that loss-of-function mutations in CWF19Ll lead to early onset cerebellar ataxia and (progressive) cerebellar atrophy. © 2016 Wiley Periodicals, Inc.

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“…Moreover, the binding affinity of PQBP1 positively correlates with the length of the poly-Q stretches of ATAXIN-1 whose hyper-expansion is associated with spinocerebellar ataxia 1 (Okazawa et al 2002). PQBP1 is known as a regulatory factor of transcription and alternative splicing (AS) by binding to various molecules at WW and CTD domains as well as to poly-Qs at the poly-Q binding domains (Mizuguchi et al 2014). Moreover, the depletion of PQBP1 in mouse neurons alters the AS pattern in mRNA enrolling neurite growth and neuron projection, such as NCAM1, resulting in a reduction of dendrite growth, which contributes to developmental stage differences in AS and causes PQBP1-related neurological disorders (Wang et al 2013).…”

Section: Repeat Expansion Diseases and Repeat Length Polymorphismmentioning

confidence: 99%

Selection pressure on human STR loci and its relevance in repeat expansion disease

et al. 2016

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Short Tandem Repeats (STRs) comprise repeats of one to several base pairs. Because of the high mutability due to strand slippage during DNA synthesis, rapid evolutionary change in the number of repeating units directly shapes the range of repeat-number variation according to selection pressure. However, the remaining questions include: Why are STRs causing repeat expansion diseases maintained in the human population; and why are these limited to neurodegenerative diseases? By evaluating the genome-wide selection pressure on STRs using the database we constructed, we identified two different patterns of relationship in repeat-number polymorphisms between DNA and amino-acid sequences, although both patterns are evolutionary consequences of avoiding the formation of harmful long STRs. First, a mixture of degenerate codons is represented in poly-proline (poly-P) repeats. Second, long poly-glutamine (poly-Q) repeats are favored at the protein level; however, at the DNA level, STRs encoding long poly-Qs are frequently divided by synonymous SNPs. Furthermore, significant enrichments of apoptosis and neurodevelopment were biological processes found specifically in genes encoding poly-Qs with repeat polymorphism. This suggests the existence of a specific molecular function for polymorphic and/or long poly-Q stretches. Given that the poly-Qs causing expansion diseases were longer than other poly-Qs, even in healthy subjects, our results indicate that the evolutionary benefits of long and/or polymorphic poly-Q stretches outweigh the risks of long CAG repeats predisposing to pathological hyper-expansions. Molecular pathways in neurodevelopment requiring long and polymorphic poly-Q stretches may provide a clue to understanding why poly-Q expansion diseases are limited to neurodegenerative diseases.

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

Cited by 33 publications

References 41 publications

Allosteric modulation of the binding affinity between PQBP1 and the spliceosomal protein U5‐15kD

Allosteric modulation of the binding affinity between PQBP1 and the spliceosomal protein U5‐15kD

Exome sequencing reveals a novel CWF19L1 mutation associated with intellectual disability and cerebellar atrophy

Selection pressure on human STR loci and its relevance in repeat expansion disease

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