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In-silico prediction of the complete ataxin-3 protein network relevant for Spinocerebellar Ataxia type 3 (SCA3)
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Abstract(s)
Spinocerebellar ataxia type 3, also known as Machado Joseph disease (SCA3/MJD), is the most common inherited ataxia worldwide and is caused by a pathogenic expansion of the polyglutamine (polyQ) tract, located at the C-terminal region of the ataxin-3 protein (1). The polyQ region is involved in the stabilization of protein- protein interactions (PPIs). Abnormal polyQ expansion results in structural changes of the ataxin-3 (2,3), implying different accessibility at specific interacting residues, needed for the normal protein activity. PolyQ proteins have large protein networks. Mapping of PPIs has been performed using high-throughput methods, that are known to produce false interactions (4). Therefore, the use of multiple interactomes comparisons (conserved interactions between pairs of proteins which have interacting homologs in another organism, as well as proteomic data from cell lines, patients, mutants expressing a human protein, and cross-species genetic screens (modifier screens), available at EvoPPI3 (5)), together with in-silico analyses, can be used to support PPIs, as well as identify novel interactors. In this work we will: 1- characterize ataxin-3 network (validating the proteins identified in main databases, as well as identify new putative interactors); 2- identifying the interactors that behave differently in the presence of an expanded polyQ using different 3D structure prediction methods and protein docking methods. Using EvoPPI3 and protein expression in tissues that matter to SCA3 for PPI retrieval and validation, as well as identification of new interactors. In-silico approaches for predicting protein binding differences between wildtype and expanded ataxin-3 forms will be performed, using different a) 3D protein structure predictions (namely ITASSER (6), AlphaFold (7), and D-ITASSER (8)) and b) protein docking methodologies (such as HADDOCK (9) and ClustPro (10). Using EvoPPI3, there are 422 ataxin-3 interactors in human main databases. From this, 250 proteins have been previously studied. Of the remaining 172 proteins, 158 have been reported from proteomic analyses of human cell lines and ataxin-3 patients (H. sapiens polyQ_22 database), and these could be true interactors. 28 proteins are in common when considering the polyQ, Mus musculus interlogs and Danio rerio interlogs, and these could be novel interactors to study. From the 158, 73 proteins bind more to the expanded form of ataxin-3 using AlphaFold, to confirm these results we used ITASSER, where we obtained 46 of the 73 that bind more to the expanded form. This study contributes significantly to understanding SCA3 pathology by delineating a network of ataxin-3 interactors and analysing their behaviour in the presence of an expanded polyQ stretch.
Description
Keywords
Ataxin-3 SCA3 polyQ protein-protein interactions In-silico methodology
Pedagogical Context
Citation
Batista, P., Vieira, J., Vieira, C. P., & Faria, B. M. (2024). In-silico prediction of the complete ataxin-3 protein network relevant for Spinocerebellar Ataxia type 3 (SCA3). Proceedings of the 1st Symposium on Biostatistics and Bioinformatics Applied to Health, 23–24. https://recipp.ipp.pt/entities/publication/a634fd4f-6053-47fa-8145-4f876572cba7
Publisher
ESS | P. PORTO Edições
CC License
Without CC licence