Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2022.10.20.513070v1?rss=1
Authors: Niccolai, N.
Abstract:
It has been recently suggested that amino acid replacements with Gly can modify the shape of protein surfaces and, hence, protein dynamics and functions. We have browsed ClinVar, the database of all the reported variants of clinical relevance, to identify all the proteins having missense X/Gly mutations that determine Mendelian disorders. We have found 959 benign and 875 pathogenic X/Gly substitutions. Pathogenicity origins were initially searched in the distribution profiles of replaced amino acids. These profiles indicate that Mendelian disorders including Gly-replacements arise mainly from substitutions of amino acids bearing bulky hydrophobic side chains, thus reducing protein core stability. In the case mutated proteins were structurally defined, we could give a deeper insight into pathogenicity mechanisms, checking whether Gly-mutations altered protein shapes, modifying water surface dynamics and, hence, the physiological protein-protein interaction processes. In several cases, indeed, we have found that pathological Gly-mutants present additional surface pockets, suggesting that the new pockets could be the target of a pharmacological strategy for Mendelian disorder remediation.
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