Frameshift PQBP-1 mutants K192Sfs7 and R153Sfs41 implicated in X-linked intellectual disability form stable dimers

[Display omitted] •Both PQBP-1 frameshift mutants are dimeric, more compact and more stable.•ab initio bead models showed overall flat shapes, probably parallel arrangement.•Ensemble models suggested folded core (WW domain) with the rest as unfolded regions.•The interactions with an RNA pol II-derived peptide were weakened in both mutants.•Homo-dimerisation of these mutants may link to loss of transcription functions. 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, K192Sfs*7 and R153Sfs*41. 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.