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      In-silico analysis of nonsynonymous genomic variants within CCM2 gene reaffirm the existence of dual cores within typical PTB domain

      brief-report
      Author(s): a , b , a , a , a , ∗
      Publication date (Electronic):
      Journal: Biochemistry and Biophysics Reports
      Publisher: Elsevier
      Keywords: In-silico analysis, Tertiary structure, Superimposition of protein structures, Amino acid substitution, Single nucleotide polymorphisms (SNPs), Nonsynonymous single nucleotide polymorphisms (nsSNPs), PTB, phosphotyrosine binding, PH, pleckstrin homology, CSC, CCM signaling complex, CCMs, cerebral cavernous malformations, PDB, protein data bank, nsSNP, nonsynonymous single nucleotide polymorphism, INDELs, insertions/deletions, PTCs, premature termination codons, SIFT, Sorting Intolerant From Tolerant, PANTHER, Protein ANalysis THrough Evolutionary Relationship, PROVEAN, Protein Variation Effect Analyzer, POLYPHEN-2, Polymorphism Phenotyping, HOPE, Have (y)Our Protein Explained, CUPSAT, Cologne University Protein Stability Analysis Tool, MAF, minor allele frequency, I-TASSER, the iterative threading assembly refinement

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          Abstract

          Purpose

          The objective of this study is to validate the existence of dual cores within the typical phosphotyrosine binding (PTB) domain and to identify potentially damaging and pathogenic nonsynonymous coding single nuclear polymorphisms (nsSNPs) in the canonical PTB domain of the CCM2 gene that causes cerebral cavernous malformations (CCMs).

          Methods

          The nsSNPs within the coding sequence for PTB domain of human CCM2 gene, retrieved from exclusive database searches, were analyzed for their functional and structural impact using a series of bioinformatic tools. The effects of mutations on the tertiary structure of the PTB domain in human CCM2 protein were predicted to examine the effect of nsSNPs on the tertiary structure of PTB Cores.

          Results

          Our mutation analysis, through alignment of protein structures between wildtype CCM2 and mutant, predicted that the structural impacts of pathogenic nsSNPs is biophysically limited to only the spatially adjacent substituted amino acid site with minimal structural influence on the adjacent core of the PTB domain, suggesting both cores are independently functional and essential for proper CCM2 PTB function.

          Conclusion

          Utilizing a combination of protein conservation and structure-based analysis, we analyzed the structural effects of inherited pathogenic mutations within the CCM2 PTB domain. Our results predicted that the pathogenic amino acid substitutions lead to only subtle changes locally, confined to the surrounding tertiary structure of the PTB core within which it resides, while no structural disturbance to the neighboring PTB core was observed, reaffirming the presence of independently functional dual cores in the CCM2 typical PTB domain.

          Highlights

          • •

            The pathogenic amino acid mutants lead to subtle structural changes in the PTB core.

          • •

            No structural disturbance to the neighboring PTB core was observed.

          • •

            Data reaffirm the presence of dual functional cores in the CCM2 PTB domain.

          • •

            More new genetic variants leading to CCM pathogenesis were suggested.

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          Most cited references47

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          UCSF Chimera--a visualization system for exploratory research and analysis.

          Eric F. Pettersen, Thomas Goddard, Conrad Huang … (2004)
          The design, implementation, and capabilities of an extensible visualization system, UCSF Chimera, are discussed. Chimera is segmented into a core that provides basic services and visualization, and extensions that provide most higher level functionality. This architecture ensures that the extension mechanism satisfies the demands of outside developers who wish to incorporate new features. Two unusual extensions are presented: Multiscale, which adds the ability to visualize large-scale molecular assemblies such as viral coats, and Collaboratory, which allows researchers to share a Chimera session interactively despite being at separate locales. Other extensions include Multalign Viewer, for showing multiple sequence alignments and associated structures; ViewDock, for screening docked ligand orientations; Movie, for replaying molecular dynamics trajectories; and Volume Viewer, for display and analysis of volumetric data. A discussion of the usage of Chimera in real-world situations is given, along with anticipated future directions. Chimera includes full user documentation, is free to academic and nonprofit users, and is available for Microsoft Windows, Linux, Apple Mac OS X, SGI IRIX, and HP Tru64 Unix from http://www.cgl.ucsf.edu/chimera/. Copyright 2004 Wiley Periodicals, Inc.
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            A method and server for predicting damaging missense mutations

            Ivan Adzhubei, Steffen Schmidt, Leonid Peshkin … (2010)
            To the Editor: Applications of rapidly advancing sequencing technologies exacerbate the need to interpret individual sequence variants. Sequencing of phenotyped clinical subjects will soon become a method of choice in studies of the genetic causes of Mendelian and complex diseases. New exon capture techniques will direct sequencing efforts towards the most informative and easily interpretable protein-coding fraction of the genome. Thus, the demand for computational predictions of the impact of protein sequence variants will continue to grow. Here we present a new method and the corresponding software tool, PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/), which is different from the early tool PolyPhen1 in the set of predictive features, alignment pipeline, and the method of classification (Fig. 1a). PolyPhen-2 uses eight sequence-based and three structure-based predictive features (Supplementary Table 1) which were selected automatically by an iterative greedy algorithm (Supplementary Methods). Majority of these features involve comparison of a property of the wild-type (ancestral, normal) allele and the corresponding property of the mutant (derived, disease-causing) allele, which together define an amino acid replacement. Most informative features characterize how well the two human alleles fit into the pattern of amino acid replacements within the multiple sequence alignment of homologous proteins, how distant the protein harboring the first deviation from the human wild-type allele is from the human protein, and whether the mutant allele originated at a hypermutable site2. The alignment pipeline selects the set of homologous sequences for the analysis using a clustering algorithm and then constructs and refines their multiple alignment (Supplementary Fig. 1). The functional significance of an allele replacement is predicted from its individual features (Supplementary Figs. 2–4) by Naïve Bayes classifier (Supplementary Methods). We used two pairs of datasets to train and test PolyPhen-2. We compiled the first pair, HumDiv, from all 3,155 damaging alleles with known effects on the molecular function causing human Mendelian diseases, present in the UniProt database, together with 6,321 differences between human proteins and their closely related mammalian homologs, assumed to be non-damaging (Supplementary Methods). The second pair, HumVar3, consists of all the 13,032 human disease-causing mutations from UniProt, together with 8,946 human nsSNPs without annotated involvement in disease, which were treated as non-damaging. We found that PolyPhen-2 performance, as presented by its receiver operating characteristic curves, was consistently superior compared to PolyPhen (Fig. 1b) and it also compared favorably with the three other popular prediction tools4–6 (Fig. 1c). For a false positive rate of 20%, PolyPhen-2 achieves the rate of true positive predictions of 92% and 73% on HumDiv and HumVar, respectively (Supplementary Table 2). One reason for a lower accuracy of predictions on HumVar is that nsSNPs assumed to be non-damaging in HumVar contain a sizable fraction of mildly deleterious alleles. In contrast, most of amino acid replacements assumed non-damaging in HumDiv must be close to selective neutrality. Because alleles that are even mildly but unconditionally deleterious cannot be fixed in the evolving lineage, no method based on comparative sequence analysis is ideal for discriminating between drastically and mildly deleterious mutations, which are assigned to the opposite categories in HumVar. Another reason is that HumDiv uses an extra criterion to avoid possible erroneous annotations of damaging mutations. For a mutation, PolyPhen-2 calculates Naïve Bayes posterior probability that this mutation is damaging and reports estimates of false positive (the chance that the mutation is classified as damaging when it is in fact non-damaging) and true positive (the chance that the mutation is classified as damaging when it is indeed damaging) rates. A mutation is also appraised qualitatively, as benign, possibly damaging, or probably damaging (Supplementary Methods). The user can choose between HumDiv- and HumVar-trained PolyPhen-2. Diagnostics of Mendelian diseases requires distinguishing mutations with drastic effects from all the remaining human variation, including abundant mildly deleterious alleles. Thus, HumVar-trained PolyPhen-2 should be used for this task. In contrast, HumDiv-trained PolyPhen-2 should be used for evaluating rare alleles at loci potentially involved in complex phenotypes, dense mapping of regions identified by genome-wide association studies, and analysis of natural selection from sequence data, where even mildly deleterious alleles must be treated as damaging. Supplementary Material 1
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              The I-TASSER Suite: protein structure and function prediction.

              Jianyi Yang, Renxiang Yan, Ambrish Roy … (2015)
              Article 0 comments Cited 1175 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Jun Zhang
                Journal
                Journal ID (nlm-ta): Biochem Biophys Rep
                Journal ID (iso-abbrev): Biochem Biophys Rep
                Title: Biochemistry and Biophysics Reports
                Publisher: Elsevier
                ISSN (Electronic): 2405-5808
                Publication date PMC-release: 27 January 2022
                Publication date Collection: March 2022
                Publication date (Electronic): 27 January 2022
                Volume: 29
                Electronic Location Identifier: 101218
                Affiliations
                [a ]Departments of Molecular & Translational Medicine (MTM), Texas Tech University Health Science Center El Paso (TTUHSCEP), El Paso, TX, 79905, USA
                [b ]Department of Neurology, University of South Alabama School of Medicine, 5795 USA N Dr., Mobile, AL, 36608, USA
                Author notes
                [∗ ]Corresponding author. Department of Molecular and Translational Medicine (MTM), Texas Tech University Health Science Center El Paso, 5001 El Paso Drive, El Paso, El Paso, TX, 79905, USA. jun.zhang2000@ 123456gmail.com
                Article
                Publisher Item ID: S2405-5808(22)00019-X Publisher ID: 101218
                DOI: 10.1016/j.bbrep.2022.101218
                PMC ID: 8808078
                PubMed ID: 35128084
                SO-VID: 1ac3d37b-530f-4edd-bb3c-4fe751a77e3d
                Copyright © © 2022 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 3 December 2021
                Date revision received : 11 January 2022
                Date accepted : 21 January 2022
                Categories
                Subject: Short Communication

                Keywords: in-silico analysis,tertiary structure,superimposition of protein structures,amino acid substitution,single nucleotide polymorphisms (snps),nonsynonymous single nucleotide polymorphisms (nssnps),ptb, phosphotyrosine binding,ph, pleckstrin homology,csc, ccm signaling complex,ccms, cerebral cavernous malformations,pdb, protein data bank,nssnp, nonsynonymous single nucleotide polymorphism,indels, insertions/deletions,ptcs, premature termination codons,sift, sorting intolerant from tolerant,panther, protein analysis through evolutionary relationship,provean, protein variation effect analyzer,polyphen-2, polymorphism phenotyping,hope, have (y)our protein explained,cupsat, cologne university protein stability analysis tool,maf, minor allele frequency,i-tasser, the iterative threading assembly refinement
                Data availability:
                Keywords: in-silico analysis, tertiary structure, superimposition of protein structures, amino acid substitution, single nucleotide polymorphisms (snps), nonsynonymous single nucleotide polymorphisms (nssnps), ptb, phosphotyrosine binding, ph, pleckstrin homology, csc, ccm signaling complex, ccms, cerebral cavernous malformations, pdb, protein data bank, nssnp, nonsynonymous single nucleotide polymorphism, indels, insertions/deletions, ptcs, premature termination codons, sift, sorting intolerant from tolerant, panther, protein analysis through evolutionary relationship, provean, protein variation effect analyzer, polyphen-2, polymorphism phenotyping, hope, have (y)our protein explained, cupsat, cologne university protein stability analysis tool, maf, minor allele frequency, i-tasser, the iterative threading assembly refinement

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