EvoPPI 1.0: a Web Platform for Within- and Between-Species Multiple Interactome Comparisons and Application to Nine PolyQ Proteins Determining Neurodegenerative Diseases

Vázquez, Noé; Rocha, Sara; López-Fernández, Hugo; Torres, André; Camacho, Rui; Fdez-Riverola, Florentino; Vieira, Jorge; Vieira, Cristina; Reboiro-Jato, Miguel

doi:10.1007/s12539-019-00317-y

Cited by 11 publications

(19 citation statements)

References 32 publications

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“…In humans, polyQ proteins tend to have more interactors than proteins lacking a polyQ tract [35, 40] which supports the view that the presence of a polyQ region increases the number of partner proteins. Nevertheless, in humans, more than 73% of the 65 genes encoding polyQ proteins are associated with diseases (Additional file 2: Table S2), and thus it is unlikely that the reported interactions are a random sample of the interactome.…”

Section: Resultsmentioning

confidence: 69%

“…Nevertheless, in humans, more than 73% of the 65 genes encoding polyQ proteins are associated with diseases (Additional file 2: Table S2), and thus it is unlikely that the reported interactions are a random sample of the interactome. Therefore, we retrieved from EvoPPI ([34, 35]; http://evoppi.i3s.up.pt), the number of interactors for the 65 human proteins that have a polyQ (a stretch with a minimum of 10 consecutive glutamines) as well as for the proteins encoded by the Mus musculus orthologs. Then, we compare the number of interactors for the proteins presenting a polyQ in both species, and those presenting a polyQ in humans only (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…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). For the between species comparison of the interactomes of ATXN1 and ATXN1L we also used EvoPPI, with the following parameters: 0.05 for the minimum expect value (evalue); 50 for the minimum length of aligment block; 40 for the minimum identity (%) and 1 for the number of descriptions (max_target_seqs) and the interaction level.…”

Section: Methodsmentioning

confidence: 99%

“…Most of the databases use different building approaches and although there is overlap between them, each presents a unique set of information [34]. Web platforms such as EvoPPI can be used to obtain all available PPI for a particular protein in a species and/or between species by performing a Blast search [34, 35]. For the human ATXN1, 311 PPI are obtained with EvoPPI when the different publicly available PPI databases are used (Additional file 1: Table S1 [35];).…”

Section: Introductionmentioning

confidence: 99%

“…Web platforms such as EvoPPI can be used to obtain all available PPI for a particular protein in a species and/or between species by performing a Blast search [34, 35]. For the human ATXN1, 311 PPI are obtained with EvoPPI when the different publicly available PPI databases are used (Additional file 1: Table S1 [35];). 165 ATXN1 PPI have been identified by performing yeast two-hybrid (Y2H) screens for proteins involved in inherited ataxias, and by validating the results using randomly sampled interacting pairs using co-affinity purification co-AP glutathione-S-transferase (GST) pull-down assays in human HEK293T cells [36].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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.

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Section: Resultsmentioning

confidence: 69%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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Atrophin‐1 Function and Dysfunction in Dentatorubral–Pallidoluysian Atrophy

et al. 2023

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Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare, incurable genetic disease that belongs to the group of polyglutamine (polyQ) diseases. DRPLA is the most common in the Japanese population; however, its global prevalence is also increasing due to better clinical recognition. It is characterized by cerebellar ataxia, myoclonus, epilepsy, dementia, and chorea. DRPLA is caused by dynamic mutation of CAG repeat expansion in ATN1 gene encoding the atrophin-1 protein. In the cascade of molecular disturbances, the pathological form of atrophin-1 is the initial factor, which has not been precisely characterized so far. Reports indicate that DRPLA is associated with disrupted protein-protein interactions (in which an expanded polyQ tract plays a crucial role), as well as gene expression deregulation. There is a great need to design efficient therapy that would address the underlying neurodegenerative process and thus prevent or alleviate DRPLA symptoms. An in-depth understanding of the normal atrophin-1 function and mutant atrophin-1 dysfunction is crucial for this purpose.

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