Reassessment of theTP53 mutation database in human disease by data mining with a library ofTP53 missense mutations

SummaryFactor XI (FXI) functions in blood coagulation. FXI is composed of four apple (Ap) domains and a serine protease (SP) domain. Deficiency of FXI leads to an injury-related bleeding disorder, which is remarkable for the lack of correlation between bleeding symptoms and FXI coagulant activity (FXI:C).The number of mutations previously reported in our interactive web database (http://www.FactorXI.org) is now significantly increased to 183 through our new patient studies and from literature surveys. Eight novel missense mutations give a total of 120 throughout the FXI gene (F11).The most abundant defects in FXI are revealed to be those from low-protein plasma levels (Type I: CRM-) that originate from protein misfolding, rather than from functional defects (Type II: CRM+). A total of 70 Ap missense mutations were analysed using a consensus Ap domain structure generated from the FXI dimer crystal structure. This showed that all parts of the Ap domain were affected.The 47 SP missense mutations were also distributed throughout the SP domain structure.The periphery of the Ap β-sheet structure is sensitive to structural perturbation caused by residue changes throughout the Ap domain, yet this β-sheet is crucial for FXI dimer formation. Residues located at the Ap4:Ap4 interface in the dimer are much less directly involved. We conclude that the abundance of Type I defects in FXI results from the sensitivity of the Ap domain folding to residue changes within this, and discuss how structural knowledge of the mutations improves our understanding of FXI deficiencies.

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Missense Mutations in Desmoplakin Plakin Repeat Domains Have Dramatic Effects on Domain Structure and Function

International Journal of Molecular Sciences ◽

10.3390/ijms23010529 ◽

2022 ◽

Vol 23 (1) ◽

pp. 529

Author(s):

Fiyaz Mohammed ◽

Elena Odintsova ◽

Martyn Chidgey

Keyword(s):

Molecular Mechanisms ◽

Structural Integrity ◽

Arrhythmogenic Right Ventricular Cardiomyopathy ◽

Bacterial Cells ◽

Missense Mutations ◽

Tissue Integrity ◽

Mutation Database ◽

Increased Risk ◽

And Function ◽

Plakin Proteins

Plakin repeat domains (PRDs) are globular modules that mediate the interaction of plakin proteins with the intermediate filament (IF) cytoskeleton. These associations are vital for maintaining tissue integrity in cardiac muscle and epithelial tissues. PRDs are subject to mutations that give rise to cardiomyopathies such as arrhythmogenic right ventricular cardiomyopathy, characterised by ventricular arrhythmias and associated with an increased risk of sudden heart failure, and skin blistering diseases. Herein, we have examined the functional and structural effects of 12 disease-linked missense mutations, identified from the human gene mutation database, on the PRDs of the desmosomal protein desmoplakin. Five mutations (G2056R and E2193K in PRD-A, G2338R and G2375R in PRD-B and G2647D in PRD-C) rendered their respective PRD proteins either fully or partially insoluble following expression in bacterial cells. Each of the residues affected are conserved across plakin family members, inferring a crucial role in maintaining the structural integrity of the PRD. In transfected HeLa cells, the mutation G2375R adversely affected the targeting of a desmoplakin C-terminal construct containing all three PRDs to vimentin IFs. The deletion of PRD-B and PRD-C from the construct compromised its targeting to vimentin. Bioinformatic and structural modelling approaches provided multiple mechanisms by which the disease-causing mutations could potentially destabilise PRD structure and compromise cytoskeletal linkages. Overall, our data highlight potential molecular mechanisms underlying pathogenic missense mutations and could pave the way for informing novel curative interventions targeting cardiomyopathies and skin blistering disorders.

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TMSNP: a web server to predict pathogenesis of missense mutations in transmembrane region of membrane proteins

10.1101/2020.01.21.913764 ◽

2020 ◽

Author(s):

Adrián Garcia-Recio ◽

José Carlos Gómez-Tamayo ◽

Iker Reina ◽

Mercedes Campillo ◽

Arnau Cordomí ◽

...

Keyword(s):

Machine Learning ◽

Membrane Proteins ◽

Genome Sequencing ◽

Web Server ◽

Prediction Tool ◽

Missense Mutations ◽

Transmembrane Region ◽

Machine Learning Model ◽

Mutation Database ◽

Mutation Prediction

AbstractThe massive amount of data generated from genome sequencing have given rise to several mutation predictor tools although no mutation database or predictor tool have been developed specifically for the transmembrane region of membrane proteins.We present TMSNP, a database that currently contains information from 2624 pathogenic and 195964 non-pathogenic reported mutations located on the TM region of membrane proteins. The computed conservation parameters and annotations on these mutations were used to train a machine-learning model that classifies TM mutations as pathogenic or non-pathogenic. The presented tool improves considerably the prediction power of commonly used mutation predictors and additionally represents the first mutation prediction tool specific for TM mutations.TMSNP is available at http://lmc.uab.es/tmsnp/[email protected]

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A Molecular Model for the Triplicated A Domains of Human Factor VIII Based on the Crystal Structure of Human Ceruloplasmin

Blood ◽

10.1182/blood.v89.7.2413 ◽

1997 ◽

Vol 89 (7) ◽

pp. 2413-2421 ◽

Cited By ~ 151

Author(s):

S. Pemberton ◽

P. Lindley ◽

V. Zaitsev ◽

G. Card ◽

E.G.D. Tuddenham ◽

...

Keyword(s):

Crystal Structure ◽

Hemophilia A ◽

Molecular Model ◽

Significant Advance ◽

Molecular Defect ◽

Missense Mutations ◽

Sequence Identity ◽

Mutation Database ◽

Human Factor Viii ◽

A Domains

Abstract The hemophilia A mutation database lists more than 160 missense mutations: each represents a molecular defect in the FVIII molecule, resulting in the X-linked bleeding disorder hemophilia A with a clinical presentation varying from mild to severe. Without a three-dimensional FVIII structure it is in most cases impossible to explain biological dysfunction in terms of the underlying molecular pathology. However, recently the crystal structure of the homologous human plasma copper-binding protein ceruloplasmin (hCp) has been solved, and the A domains of FVIII share approximately 34% sequence identity with hCp. This advance has enabled the building of a molecular model of the A domains of FVIII based on the sequence identity between the two proteins. The model allows exploration of predictions regarding the general features of the FVIII molecule, such as the binding-sites for factor IXa and activated protein C; it has also allowed the mapping of more than 30 selected mutations with known phenotype from the database, and the prediction of hypothetical links to dysfunction in all but a few cases. A computer-generated molecular model such as that reported here cannot substitute for a crystal structure. However, until such a structure for FVIII becomes available, the model represents a significant advance in modeling FVIII; it should prove a useful tool for exploiting the increasing amount of information in the hemophilia A mutation database, and for selecting appropriate targets for investigation of the structure-function relationships via mutagenesis and expression in vitro.

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