MISCAST: MIssense variant to protein StruCture Analysis web SuiTe

Iqbal, Sumaiya; Hoksza, David; Pérez‐Palma, Eduardo; Jespersen, Jakob Berg; Ahmed, Shehab; Rifat, Zaara Tasnim; Heyne, Henrike O.; Rahman, M. Sohel; Cottrell, Jeffrey R.; Wagner, Florence F.; Daly, Mark J.; Campbell, Arthur J.; Lal, Dennis

doi:10.1093/nar/gkaa361

Cited by 19 publications

(18 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 14 In a further approach, the MISCAST suite provides an approach to connect probabilities of loss of function with primary sequence level features. 15 …”

Section: Introductionmentioning

confidence: 99%

Missense Variants Reveal Functional Insights Into the Human ARID Family of Gene Regulators

Deák

Cook

2022

Journal of Molecular Biology

View full text Add to dashboard Cite

“… 14 In a further approach, the MISCAST suite provides an approach to connect probabilities of loss of function with primary sequence level features. 15 …”

Section: Introductionmentioning

confidence: 99%

Missense Variants Reveal Functional Insights Into the Human ARID Family of Gene Regulators

Deák

Cook

2022

Journal of Molecular Biology

View full text Add to dashboard Cite

“…Here, “pathogenicity” is curated based on literature references, according to the referenced version of the Humsavar database, and “the number of contacts” describes the number of residues contacting the WT residue at the mutated position, with a cutoff of 6 or more heavy atom contacts of any type within 5 Å. Further, the MISCAST database 5 was referenced for the set of mutations that are mappable to protein structures and are common between ADDRESS and MISCAST to explore the relationship of circuit topological information to additional structural features.…”

Section: Methodsmentioning

confidence: 99%

“…One mechanism by which missense mutations can cause disease is by altering the folding properties of the protein in which the amino acid change is located. Databases of pathogenic and benign mutations have been established, where the domain of the protein containing the mutation can often be linked to a crystal structure or NMR structure in the Protein Data Bank 1–5 . However, it is still a challenge to predict whether a given mutation will lead to disease, suggesting that common measures such as ∆∆ G , the change in free energy of folding upon mutation, 6 may not account for all the relevant information contained in the structure 7,8 .…”

Section: Introductionmentioning

confidence: 99%

Circuit topology predicts pathogenicity of missense mutations

2022

Self Cite

View full text Add to dashboard Cite

The contact topology of a protein determines important aspects of the folding process. The topological measure of contact order has been shown to be predictive of the rate of folding. Circuit topology is emerging as another fundamental descriptor of biomolecular structure, with predicted effects on the folding rate. We analyze the residue-based circuit topological environments of 21 K mutations labeled as pathogenic or benign. Multiple statistical lines of reasoning support the conclusion that the number of contacts in two specific circuit topological arrangements, namely inverse parallel and cross relations, with contacts involving the mutated residue have discriminatory value in determining the pathogenicity of human variants. We investigate how results vary with residue type and according to whether the gene is essential.We further explore the relationship to a number of structural features and find that circuit topology provides nonredundant information on protein structures and pathogenicity of mutations. Results may have implications for the polymer physics of protein folding and suggest that "local" topological information, including residue-based circuit topology and residue contact order, could be useful in improving state-of-theart machine learning algorithms for pathogenicity prediction.

show abstract

“…All analyses were performed in R Studio (Version 1.2.1335, 2009–2019 RStudio, Inc., Boston, Massachuttes) using the tidyr package [ 51 ]. Consensus RSA values for all MTOR residues were downloaded from the MISCAST database Variant Analysis Suite on April 25, 2020 ( http://miscast.broadinstitute.org/ ) [ 52 ]. To calculate accessible surface area (ASA) for individual MTOR structures, monomers of chain A of structures with Protein Data Bank codes 6BCX and 6BCU (activated by Ras homolog enriched in brain) were generated.…”

Section: Methodsmentioning

confidence: 99%

Functional and structural analyses of novel Smith-Kingsmore Syndrome-Associated MTOR variants reveal potential new mechanisms and predictors of pathogenicity

et al. 2021

View full text Add to dashboard Cite

Smith-Kingsmore syndrome (SKS) is a rare neurodevelopmental disorder characterized by macrocephaly/megalencephaly, developmental delay, intellectual disability, hypotonia, and seizures. It is caused by dominant missense mutations in MTOR. The pathogenicity of novel variants in MTOR in patients with neurodevelopmental disorders can be difficult to determine and the mechanism by which variants cause disease remains poorly understood. We report 7 patients with SKS with 4 novel MTOR variants and describe their phenotypes. We perform in vitro functional analyses to confirm MTOR activation and interrogate disease mechanisms. We complete structural analyses to understand the 3D properties of pathogenic variants. We examine the accuracy of relative accessible surface area, a quantitative measure of amino acid side-chain accessibility, as a predictor of MTOR variant pathogenicity. We describe novel clinical features of patients with SKS. We confirm MTOR Complex 1 activation and identify MTOR Complex 2 activation as a new potential mechanism of disease in SKS. We find that pathogenic MTOR variants disproportionately cluster in hotspots in the core of the protein, where they disrupt alpha helix packing due to the insertion of bulky amino acid side chains. We find that relative accessible surface area is significantly lower for SKS-associated variants compared to benign variants. We expand the phenotype of SKS and demonstrate that additional pathways of activation may contribute to disease. Incorporating 3D properties of MTOR variants may help in pathogenicity classification. We hope these findings may contribute to improving the precision of care and therapeutic development for individuals with SKS.

show abstract

MISCAST: MIssense variant to protein StruCture Analysis web SuiTe

Cited by 19 publications

References 34 publications

Missense Variants Reveal Functional Insights Into the Human ARID Family of Gene Regulators

Missense Variants Reveal Functional Insights Into the Human ARID Family of Gene Regulators

Circuit topology predicts pathogenicity of missense mutations

Functional and structural analyses of novel Smith-Kingsmore Syndrome-Associated MTOR variants reveal potential new mechanisms and predictors of pathogenicity

Contact Info

Product

Resources

About