Work

Functional and Structural Characterization of Pathogenicity of Human Arginine-Histidine Variants

Year: 2025

Type: article

Abstract: Missense variants that change arginine-to-histidine and histidine-to-arginine ([Formula: see text] > [Formula: see text]; [Formula: see text] > [Formula: see text] preserve positive charge yet alter pH-dependent behavior near neutrality, creating mutation type-specific but context-dependent effects on protein function, and thus could be pathogenic. To reveal the factors causing pathogenicity, we assembled high-confidence human [Formula: see text] > [Formula: see text] and [Formula: see text] > [Formula: see text] variants from ClinVar annotated as pathogenic or benign. It was found that in both cases, [Formula: see text] > [Formula: see text]/[Formula: see text] > [Formula: see text], pathogenic variants are strongly enriched in cores and ordered regions, while benign variants were seen on surfaces and coils. Secondary structure analysis showed mutation type specificity; [Formula: see text] > [Formula: see text] pathogenic variants were enriched in helices, while [Formula: see text] > [Formula: see text] pathogenic variants were enriched in [Formula: see text]-strands. Regarding the pH-optimum of activity, most [Formula: see text] > [Formula: see text] and [Formula: see text] > [Formula: see text] variants fell in physiological/near-physiological pH ranges, but [Formula: see text] > [Formula: see text] benign variants were more frequent in the neutral/physiological pH bin, whereas [Formula: see text] > [Formula: see text] pathogenic variants were overrepresented in the same neutral/physiological pH range. The last observation is consistent with histidine’s pK[Formula: see text] being tunable near physiological range, while arginine’s side chain introduces a permanent positive charge, and thus [Formula: see text] > [Formula: see text] substitution eliminates the wild-type pH-dependence. Functional protein analyses highlighted that pathogenic variants are overrepresented at binding/interface-heavy proteins (e.g., transcription factors) and selected enzymatic classes (e.g., oxidoreductases, ion channels, transporters, ligases). Interestingly, in the vast majority of cases, the proteins in our dataset had either [Formula: see text] > [Formula: see text] or [Formula: see text] > [Formula: see text] mutations, but not both present in the same protein. Proteins harboring both variant types, [Formula: see text] > [Formula: see text] and [Formula: see text] > [Formula: see text], were very few, and typically they had both variants, either pathogenic or benign.

Source: Journal of Computational Biophysics and Chemistry

DOI: 10.1142/s2737416526400041

Authors: Nirav Modha, Emil Alexov

Institution: Clemson University

Language: English

Topic: Genomics and Rare Diseases

Subfield: Genetics

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

Funder: National Institute of General Medical Sciences