ATXN1 N-terminal region explains the binding differences of wild-type and expanded forms

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.

The Josephin domain (JD) containing proteins are predicted to bind to the same interactors: Implications for spinocerebellar ataxia type 3 (SCA3) studies using Drosophila melanogaster mutants

“…The interaction regions between ataxin-3 and 150 selected interactors (35% of the total network; Supplementary Table S4 ), JosL and four fly interactors ( Supplementary Table S5 ), JosL and 45 fly ataxin-3 modifier genes for which the human paralogs code for an ataxin-3 interactor (28% of the total network; Supplementary Table S6 ), JOS1 and 37 JOS1 interactors ( Supplementary Table S7 ), JOS1 and 126 ataxin-3 interactors not reported as JOS1 interactors, JOS2 and 17 JOS2 interactors ( Supplementary Table S7 ), and JOS2 and 129 ataxin-3 interctors not reported as JOS2 interactors were predicted using the in-silico methodology, described by Rocha et al (2019) .…”

“…It should be noted that this data is not available in the main PPI databases for humans, since these are interactions between proteins from different species, and thus it is unclear whether the interactions of the homologous proteins are present in humans. Since there is no ATXN3 lineage gene in Drosophila, and there is only one Josephin-like gene ( Weeks et al, 2011 ), here we address whether mutant ATXN3 flies are a good model for SCA3, by comparing the ataxin-3 interaction regions of human and fly homologous proteins, using the in-silico approach of Rocha et al (2019) .…”

“…The C-terminal region, in particular the NLS site, is however, essential for VCP/p97 interaction ( Fujita et al, 2013 ; Matos et al, 2019 ). The relative frequency of use of the different ataxin-3 interacting regions is, however, unknown, and here we address this issue by performing in-silico protein–protein docking analyses ( Rocha et al, 2019 ) using 150 ataxin-3 interactors.…”

“…PolyQ regions are located between a disordered region and a coiled-coil region used for PPI ( Schaefer et al, 2012 ; Mier and Andrade-Navarro, 2021 ), and when expanded, this region is hypothesized to adopt a helical conformation, extending the preceding helix, and thus making the PPI stronger ( Schaefer et al, 2012 ; Petrakis et al, 2013 ; Mier and Andrade-Navarro, 2021 ). These structural changes of the protein ( Takeuchi and Nagai, 2017 ) lead to different accessibility at specific interacting residues that are needed for the normal protein activity ( Lim et al, 2006 ; Araujo et al, 2011 ; Suter et al, 2013 ; Hosp et al, 2015 ; Silva et al, 2018 ; Rocha et al, 2019 ). To address this issue comparative in-silico protein–protein docking analyses have been performed, using the pathogenic (exp) and the wild type (wt) ataxin-3 forms.…”

The evolution of vitamin C biosynthesis and transport in animals

“…Protein docking inferences were performed using an in silico protocol available in the literature [ 86 ]. The D. melanogaster protein sequences were downloaded from NCBI as FASTA formatted files (accession numbers AAN09306.2 (Regucalcin), AGB95961.1 (Dca), NP_608711.3 (Histidine triad nucleotide binding protein 1), NP_476735.1 (Superoxide dismutase 1), and NP_732311.1 (14-3-3epsilon)).…”