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TitleFrameshift PQBP-1 mutants K192S and R153S implicated in X-linked intellectual disability form stable dimers.
Journal, issue, pagesJ Struct Biol, Vol. 206, Issue 3, Page 305-313, Year 2019
Publish dateJun 1, 2019
AuthorsShah Kamranur Rahman / Hitoshi Okazawa / Yu Wai Chen /
PubMed AbstractPolyglutamine tract-binding protein-1 (PQBP-1) is a nuclear intrinsically disordered protein playing important roles in transcriptional regulation and RNA splicing during embryonic and postembryonic ...Polyglutamine tract-binding protein-1 (PQBP-1) is a nuclear intrinsically disordered protein playing important roles in transcriptional regulation and RNA splicing during embryonic and postembryonic development. In human, its mutations lead to severe cognitive impairment known as the Renpenning syndrome, a form of X-linked intellectual disability (XLID). Here, we report a combined biophysical study of two PQBP-1 frameshift mutants, K192S and R153S. Both mutants are dimeric in solution, in contrast to the monomeric wild-type protein. These mutants contain more folded contents and have increased thermal stabilities. Using small-angle X-ray scattering data, we generated three-dimensional envelopes which revealed their overall flat shapes. We also described each mutant using an ensemble model based on a native-like initial pool with a dimeric structural core. PQBP-1 is known to repress transcription by way of interacting with the C-terminal domain of RNA polymerase II, which consists of 52 repeats of a consensus heptapeptide sequence YSPTSPS. We studied the binding of PQBP-1 variants to the labelled peptide which is phosphorylated at positions 2 and 5 (YpSPTpSPS) and found that this interaction is significantly weakened in the two mutants.
External linksJ Struct Biol / PubMed:30951824
MethodsSAS (X-ray synchrotron)
Structure data

SASDET6:
Polyglutamine-binding protein 1 p.Lys192Serfs*7 (PQBP-1 XLID mutant K192Sfs*7)
Method: SAXS/SANS

SASDEU6:
Polyglutamine-binding protein 1 p.Arg153Serfs*41 (PQBP-1 XLID mutant R153Sfs*41)
Method: SAXS/SANS

Source
  • Homo sapiens (human)

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