On Human Disease-Causing Amino Acid Variants: Statistical Study of Sequence and Structural Patterns

Petukh, Marharyta; Kucukkal, Tugba G.; Alexov, Emil

doi:10.1002/humu.22770

Cited by 139 publications

(132 citation statements)

References 95 publications

(156 reference statements)

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“…S1). A recent study showed that disease-causing mutations often change the number of hydrogen-bonds and salt bridges in comparison to nondisease-causing counterparts (37). In line with this, we found that the E50K mutation on BCAP decreased the number of intermolecular H-bonds by 1 and salt bridges by 2 in the BCAP-TLR4 interaction.…”

Section: Bcapsupporting

confidence: 77%

A Structural View of Negative Regulation of the Toll-like Receptor-Mediated Inflammatory Pathway

Guven-Maiorov

Keskin

Gürsoy

et al. 2015

Biophysical Journal

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Even though the Toll-like receptor (TLR) pathway is integral to inflammatory defense mechanisms, its excessive signaling may be devastating. Cells have acquired a cascade of strategies to regulate TLR signaling by targeting protein-protein interactions, or ubiquitin chains, but the details of the inhibition mechanisms are still unclear. Here, we provide the structural basis for the regulation of TLR signaling by constructing architectures of protein-protein interactions. Structural data suggest that 1) Toll/IL-1R (TIR) domain-containing regulators (BCAP, SIGIRR, and ST2) interfere with TIR domain signalosome formation; 2) major deubiquitinases such as A20, CYLD, and DUBA prevent association of TRAF6 and TRAF3 with their partners, in addition to removing K63-linked ubiquitin chains that serve as a docking platform for downstream effectors; 3) alternative downstream pathways of TLRs also restrict signaling by competing to bind common partners through shared binding sites. We also performed in silico mutagenesis analysis to characterize the effects of oncogenic mutations on the negative regulators and to observe the cellular outcome (whether there is/is not inflammation). Missense mutations that fall on interfaces and nonsense/frameshift mutations that result in truncated negative regulators disrupt the interactions with the targets, thereby enabling constitutive activation of the nuclear factor-kappa B, and contributing to chronic inflammation, autoimmune diseases, and oncogenesis.

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Section: Bcapsupporting

confidence: 77%

A Structural View of Negative Regulation of the Toll-like Receptor-Mediated Inflammatory Pathway

Guven-Maiorov

Keskin

Gürsoy

et al. 2015

Biophysical Journal

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“…The protein structure stability plays a predominant role in maintaining the functionality of a protein25. A mutation can affect the protein stability (both destabilizing and over stabilizing) leading to deterioration of the protein function through physico-chemical properties changes of the mutant amino acids (charge, size, hydrophobicity, hydrogen bonds)26. In recent years, MDSA has proved to be a powerful tool in elucidating the changes in a macromolecule at an atomistic level, thereby rendering better prediction results27282930.…”

Section: Discussionmentioning

confidence: 99%

Genetic Epidemiology of Glucose-6-Phosphate Dehydrogenase Deficiency in the Arab World

Alasmar

Bux

et al. 2016

Sci Rep

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A systematic search was implemented using four literature databases (PubMed, Embase, Science Direct and Web of Science) to capture all the causative mutations of Glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDD) in the 22 Arab countries. Our search yielded 43 studies that captured 33 mutations (23 missense, one silent, two deletions, and seven intronic mutations), in 3,430 Arab patients with G6PDD. The 23 missense mutations were then subjected to phenotypic classification using in silico prediction tools, which were compared to the WHO pathogenicity scale as a reference. These in silico tools were tested for their predicting efficiency using rigorous statistical analyses. Of the 23 missense mutations, p.S188F, p.I48T, p.N126D, and p.V68M, were identified as the most common mutations among Arab populations, but were not unique to the Arab world, interestingly, our search strategy found four other mutations (p.N135T, p.S179N, p.R246L, and p.Q307P) that are unique to Arabs. These mutations were exposed to structural analysis and molecular dynamics simulation analysis (MDSA), which predicting these mutant forms as potentially affect the enzyme function. The combination of the MDSA, structural analysis, and in silico predictions and statistical tools we used will provide a platform for future prediction accuracy for the pathogenicity of genetic mutations.

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“…The G→R substitution in the G121R and G291R mutants is one of the more dramatic physicochemical changes among the disease-related variants of PGM1 [15], and is also one of the two variants most frequently associated with human disease in general [25,26]. Given the obvious differences between glycine and arginine, structural repercussions on the enzyme are not unexpected.…”

Section: Discussionmentioning

confidence: 99%

Induced Structural Disorder as a Molecular Mechanism for Enzyme Dysfunction in Phosphoglucomutase 1 Deficiency

Stiers

Kain

Graham

et al. 2016

Journal of Molecular Biology

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Human phosphoglucomutase 1 (PGM1) plays a central role in cellular glucose homeostasis, mediating the switch between glycolysis and gluconeogenesis through the conversion of glucose 1-phosphate and glucose 6-phosphate. Recent clinical studies have identified mutations in this enzyme as the cause of PGM1 deficiency, an inborn error of metabolism classified as both a glycogen storage disease and a congenital disorder of glycosylation. Reported here are the first crystal structures of two disease-related missense variants of PGM1, along with the structure of the wild-type enzyme. Two independent glycine to arginine substitutions (G121R and G291R), both affecting key active site loops of PGM1, are found to induce regions of structural disorder, as evidenced by a nearly complete loss of electron density for as many as 23 amino acids. The disordered regions are not contiguous in sequence to the site of mutation, and even cross domain boundaries. Other structural rearrangements include changes in the conformations of loops and side chains, some of which occur nearly 20 Å away from the site of mutation. The induced structural disorder is correlated with increased sensitivity to proteolysis and lower resolution diffraction, particularly for the G291R variant. Examination of the multi-domain effects of these G→R mutations establishes a correlation between interdomain interfaces of the enzyme and missense variants of PGM1 associated with disease. These crystal structures provide the first insights into the structural basis of enzyme dysfunction in PGM1 deficiency, and highlight a growing role for biophysical characterization of proteins in the field of precision medicine.

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On Human Disease-Causing Amino Acid Variants: Statistical Study of Sequence and Structural Patterns

Cited by 139 publications

References 95 publications

A Structural View of Negative Regulation of the Toll-like Receptor-Mediated Inflammatory Pathway

A Structural View of Negative Regulation of the Toll-like Receptor-Mediated Inflammatory Pathway

Genetic Epidemiology of Glucose-6-Phosphate Dehydrogenase Deficiency in the Arab World

Induced Structural Disorder as a Molecular Mechanism for Enzyme Dysfunction in Phosphoglucomutase 1 Deficiency

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