Abstract
BackgroundWild-type (wt) polyglutamine (polyQ) regions are implicated in stabilization of protein-protein interactions (PPI). Pathological polyQ expansion, such as that in human Ataxin-1 (ATXN1), that causes spinocerebellar ataxia type 1 (SCA1), results in abnormal PPI. For ATXN1 a larger number of interactors has been reported for the expanded (82Q) than the wt (29Q) protein.MethodsTo understand how the expanded polyQ affects PPI, protein structures were predicted for wt and expanded ATXN1, as well as, for 71 ATXN1 interactors. Then, the binding surfaces of wt and expanded ATXN1 with the reported interactors were inferred.ResultsOur data supports that the polyQ expansion alters the ATXN1 conformation and that it enhances the strength of interaction with ATXN1 partners. For both ATXN1 variants, the number of residues at the predicted binding interface are greater after the polyQ, mainly due to the AXH domain. Moreover, the difference in the interaction strength of the ATXN1 variants was due to an increase in the number of interactions at the N-terminal region, before the polyQ, for the expanded form.ConclusionsThere are three regions at the AXH domain that are essential for ATXN1 PPI. The N-terminal region is responsible for the strength of the PPI with the ATXN1 variants. How the predicted motifs in this region affect PPI is discussed, in the context of ATXN1 post-transcriptional modifications.
Highlights
Wild-type polyglutamine regions are implicated in stabilization of protein-protein interactions (PPI)
ATXN1 PPI H. sapiens, M. musculus, X. laevis, D. rerio, D. melanogaster, and C. elegans ATXN1 and ATXN1L PPI have been retrieved from EvoPPI ([34, 35]; http://evoppi.i3s.up.pt); accession numbers are listed in Additional file 10: Table S5)
In humans, more than 73% of the 65 genes encoding polyQ proteins are associated with diseases (Additional file 2: Table S2), and it is unlikely that the reported interactions are a random sample of the interactome
Summary
Wild-type (wt) polyglutamine (polyQ) regions are implicated in stabilization of protein-protein interactions (PPI). There are nine polyglutamine (polyQ) diseases caused by expansion of a trinucleotide CAG repeat giving rise to a protein with a repeated polyQ tract that extends over its physiological length [1,2,3,4]. Based on sequence conservation between species and secondary structure prediction, the globular AXH domain (residues 562– 693) has been identified [8]. This domain is involved in interactions of the ATXN1 with itself, as well as the majority of the identified ATXN1 interactors [9,10,11,12,13]. The self-association region (SAR, residues 494–604, [14]), the
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