Characterization of the impact of alternative splicing on protein dynamics: The cases of glutathione S‐transferase and ectodysplasin‐A isoforms

Barbany, Montserrat; Morata, Jordi; Meyer, Tim; Lois, Sergio; Orozco, Modesto; Cruz, Xavier de la

doi:10.1002/prot.24112

Cited by 5 publications

(10 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…there is no single time interval that would allow us to retrieve all the couplings. The 200ps value was chosen on the basis of our previous work[ 34 ], where for an analogous problem (involving correlations between SURFNET cavities) we were able to find a substantial number of couplings. For D41 trajectories, we had two sampling steps: for the 100 ns trajectories, we collected one snapshot every 200ps; for ~1 microsecond simulations, we collected one snapshot every 2000ps.…”

Section: Methodsmentioning

confidence: 99%

“…We followed our previous protocol[ 17 ] (see below), in which cavities are computed with the program SURFNET[ 35 ]. Apart from SURFNET there are different ways of identifying protein cavities: Pass[ 36 ]; Fpocket[ 37 ]/MDpocket[ 38 ]; etc.…”

Section: Methodsmentioning

confidence: 99%

“…We decided to use SURFNET because it is broadly used and cited in structure/function studies and its cavities cover a large range of sizes. In addition, SURFNET has been used in many cases to support or define the structure/function analysis of MD trajectories[ 34 , 39 – 42 ]. In this sense, it is worth noting that Pesce et al[ 43 ] find an excellent agreement between SURFNET cavities and the observation of bound Xe and butyl-isocyanide molecules in their study of myoglobin and truncated hemoglobins.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Molecular Dynamics Study of Naturally Existing Cavity Couplings in Proteins

et al. 2015

Self Cite

View full text Add to dashboard Cite

Couplings between protein sub-structures are a common property of protein dynamics. Some of these couplings are especially interesting since they relate to function and its regulation. In this article we have studied the case of cavity couplings because cavities can host functional sites, allosteric sites, and are the locus of interactions with the cell milieu. We have divided this problem into two parts. In the first part, we have explored the presence of cavity couplings in the natural dynamics of 75 proteins, using 20 ns molecular dynamics simulations. For each of these proteins, we have obtained two trajectories around their native state. After applying a stringent filtering procedure, we found significant cavity correlations in 60% of the proteins. We analyze and discuss the structure origins of these correlations, including neighbourhood, cavity distance, etc. In the second part of our study, we have used longer simulations (≥100ns) from the MoDEL project, to obtain a broader view of cavity couplings, particularly about their dependence on time. Using moving window computations we explored the fluctuations of cavity couplings along time, finding that these couplings could fluctuate substantially during the trajectory, reaching in several cases correlations above 0.25/0.5. In summary, we describe the structural origin and the variations with time of cavity couplings. We complete our work with a brief discussion of the biological implications of these results.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Molecular Dynamics Study of Naturally Existing Cavity Couplings in Proteins

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…Because the experimental approach required to provide an answer for the thousands of known isoforms is so complex, these questions are still open. On one side, studies carried in specific systems [96]–[100] support the functional role of IM. This is also supported by large-scale studies.…”

Section: Discussionmentioning

confidence: 94%

The Relationship between Gene Isoform Multiplicity, Number of Exons and Protein Divergence

et al. 2013

Self Cite

View full text Add to dashboard Cite

At present we know that phenotypic differences between organisms arise from a variety of sources, like protein sequence divergence, regulatory sequence divergence, alternative splicing, etc. However, we do not have yet a complete view of how these sources are related. Here we address this problem, studying the relationship between protein divergence and the ability of genes to express multiple isoforms. We used three genome-wide datasets of human-mouse orthologs to study the relationship between isoform multiplicity co-occurrence between orthologs (the fact that two orthologs have more than one isoform) and protein divergence. In all cases our results showed that there was a monotonic dependence between these two properties. We could explain this relationship in terms of a more fundamental one, between exon number of the largest isoform and protein divergence. We found that this last relationship was present, although with variations, in other species (chimpanzee, cow, rat, chicken, zebrafish and fruit fly). In summary, we have identified a relationship between protein divergence and isoform multiplicity co-occurrence and explained its origin in terms of a simple gene-level property. Finally, we discuss the biological implications of these findings for our understanding of inter-species phenotypic differences.

show abstract

“…Ultimately, we identified the EGFR (epidermal growth factor receptor) and mTOR (mammalian target of rapamycin) signaling pathway as the molecular network most associated with neural alternative splicing. The EGFR/mTOR pathway is an important cellular signaling pathway that controls cell growth and proliferation [ 16 , 24 ]. This pathway has been intensively studied, and many of the proteins involved have been identified.…”

Section: Introductionmentioning

confidence: 99%

Computational extraction of a neural molecular network through alternative splicing

et al. 2014

View full text Add to dashboard Cite

BackgroundGenerally, the results of high throughput analyses contain information about gene expressions, and about exon expressions. Approximately 90% of primary protein-coding transcripts undergo alternative splicing in mammals. However, changes induced by alternative exons have not been properly analyzed for their impact on important molecular networks or their biological events. Even when alternative exons are identified, they are usually subjected to bioinformatics analysis in the same way as the gene ignoring the possibility of functionality change because of the alteration of domain caused by alternative exon. Here, we reveal an effective computational approach to explore an important molecular network based on potential changes of functionality induced by alternative exons obtained from our comprehensive analysis of neuronal cell differentiation.ResultsFrom our previously identified 262 differentially alternatively spliced exons during neuronal cell differentiations, we extracted 241 sets that changed the amino acid sequences between the alternatively spliced sequences. Conserved domain searches indicated that annotated domain(s) were changed in 128 sets. We obtained 49 genes whose terms overlapped between domain description and gene annotation. Thus, these 49 genes have alternatively differentially spliced in exons that affect their main functions. We performed pathway analysis using these 49 genes and identified the EGFR (epidermal growth factor receptor) and mTOR (mammalian target of rapamycin) signaling pathway as being involved frequently. Recent studies reported that the mTOR pathway is associated with neuronal cell differentiation, vindicating that our approach extracted an important molecular network successfully.ConclusionsEffective informatics approaches for exons should be more complex than those for genes, because changes in alternative exons affect protein functions via alterations of amino acid sequences and functional domains. Our method extracted alterations of functional domains and identified key alternative splicing events. We identified the EGFR and mTOR signaling pathway as the most affected pathway. The mTOR pathway is important for neuronal differentiation, suggesting that this in silico extraction of alternative splicing networks is useful. This preliminary analysis indicated that automated analysis of the effects of alternative splicing would provide a rich source of biologically relevant information.Electronic supplementary materialThe online version of this article (doi:10.1186/1756-0500-7-934) contains supplementary material, which is available to authorized users.

show abstract

Characterization of the impact of alternative splicing on protein dynamics: The cases of glutathione S‐transferase and ectodysplasin‐A isoforms

Cited by 5 publications

References 54 publications

Molecular Dynamics Study of Naturally Existing Cavity Couplings in Proteins

Molecular Dynamics Study of Naturally Existing Cavity Couplings in Proteins

The Relationship between Gene Isoform Multiplicity, Number of Exons and Protein Divergence

Computational extraction of a neural molecular network through alternative splicing

Contact Info

Product

Resources

About