INPS: predicting the impact of non-synonymous variations on protein stability from sequence

Fariselli, Piero; Martelli, Pier Luigi; Savojardo, Castrense; Casadio, Rita

doi:10.1093/bioinformatics/btv291

Cited by 129 publications

(155 citation statements)

References 32 publications

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“…30 The effect of missense mutations on protein stability was assessed using the Impact of Non-synonymous mutations on Protein Stability (INPS) server. 31 …”

Section: Protein Alignment and Structural Modelingmentioning

confidence: 99%

Germ line mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia

Speedy

Kinnersley

Chubb

et al. 2016

Blood

103

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Key Points• Germ line loss-of-function mutations in shelterin genes occur in a subset of families with CLL.• Telomere dysregulation is further implicated in CLL predisposition.Chronic lymphocytic leukemia (CLL) can be familial; however, thus far no rare germ line disruptive alleles for CLL have been identified. We performed whole-exome sequencing of 66 CLL families, identifying 4 families where loss-of-function mutations in protection of telomeres 1 (POT1) co-segregated with CLL. The p.Tyr36Cys mutation is predicted to disrupt the interaction between POT1 and the telomeric overhang. The c.1164-1G>A splice-site, p.Gln358SerfsTer13 frameshift, and p.Gln376Arg missense mutations are likely to impact the interaction between POT1 and adrenocortical dysplasia homolog (ACD), which is a part of the telomere-capping shelterin complex. We also identified mutations in ACD (c.752-2A>C) and another shelterin component, telomeric repeat binding factor 2, interacting protein (p.Ala104Pro and p.Arg133Gln), in 3 CLL families. In a complementary analysis of 1083 cases and 5854 controls, the POT1 p.Gln376Arg variant, which has a global minor allele frequency of 0.0005, conferred a 3.61-fold increased risk of CLL (P 5

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“…30 The effect of missense mutations on protein stability was assessed using the Impact of Non-synonymous mutations on Protein Stability (INPS) server. 31 …”

Section: Protein Alignment and Structural Modelingmentioning

confidence: 99%

Germ line mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia

Speedy

Kinnersley

Chubb

et al. 2016

Blood

103

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“…Experimental [25,27,28,40] and computational [47,48,49,50] studies on several proteins related the effect of nsSNPs to the alteration of protein stability, protein–protein interactions, and protein functions. The interest in studying the effects of nsSNPs on structural stability and dynamic properties of PPARγ derives from the involvement of this nuclear receptor in a variety of biological processes such as adipocyte differentiation and insulin sensitization, as well as cellular differentiation and development and carcinogenesis [14].…”

Section: Discussionmentioning

confidence: 99%

Single-Nucleotide Polymorphism of PPARγ, a Protein at the Crossroads of Physiological and Pathological Processes

Petrosino

Lori

Pasquo

et al. 2017

IJMS

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Genome polymorphisms are responsible for phenotypic differences between humans and for individual susceptibility to genetic diseases and therapeutic responses. Non-synonymous single-nucleotide polymorphisms (nsSNPs) lead to protein variants with a change in the amino acid sequence that may affect the structure and/or function of the protein and may be utilized as efficient structural and functional markers of association to complex diseases. This study is focused on nsSNP variants of the ligand binding domain of PPARγ a nuclear receptor in the superfamily of ligand inducible transcription factors that play an important role in regulating lipid metabolism and in several processes ranging from cellular differentiation and development to carcinogenesis. Here we selected nine nsSNPs variants of the PPARγ ligand binding domain, V290M, R357A, R397C, F360L, P467L, Q286P, R288H, E324K, and E460K, expressed in cancer tissues and/or associated with partial lipodystrophy and insulin resistance. The effects of a single amino acid change on the thermodynamic stability of PPARγ, its spectral properties, and molecular dynamics have been investigated. The nsSNPs PPARγ variants show alteration of dynamics and tertiary contacts that impair the correct reciprocal positioning of helices 3 and 12, crucially important for PPARγ functioning.

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“…INPS (Fariselli et al, ) is a method for predicting the impact of SAVs on protein stability starting from protein sequence. In particular, it estimates the difference of Gibbs free energy change (Δ G ) between wild‐type and variant proteins (ΔΔ G ).…”

Section: Methodsmentioning

confidence: 99%

Are machine learning based methods suited to address complex biological problems? Lessons from CAGI‐5 challenges

et al. 2019

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In silico approaches are routinely adopted to predict the effects of genetic variants and their relation to diseases. The critical assessment of genome interpretation (CAGI) has established a common framework for the assessment of available predictors of variant effects on specific problems and our group has been an active participant of CAGI since its first edition. In this paper, we summarize our experience and lessons learned from the last edition of the experiment (CAGI‐5). In particular, we analyze prediction performances of our tools on five CAGI‐5 selected challenges grouped into three different categories: prediction of variant effects on protein stability, prediction of variant pathogenicity, and prediction of complex functional effects. For each challenge, we analyze in detail the performance of our tools, highlighting their potentialities and drawbacks. The aim is to better define the application boundaries of each tool.

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INPS: predicting the impact of non-synonymous variations on protein stability from sequence

Abstract: Supplementary Materials are available at Bioinformatics online.

Cited by 129 publications

References 32 publications

Germ line mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia

Germ line mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia

Single-Nucleotide Polymorphism of PPARγ, a Protein at the Crossroads of Physiological and Pathological Processes

Are machine learning based methods suited to address complex biological problems? Lessons from CAGI‐5 challenges

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