Protein dynamics analysis reveals that missense mutations in cancer-related genes appear frequently on hinge-neighboring residues

Proteins
Jan Fehmi SayılganMehmet Gönen

Abstract

Missense mutations have various effects on protein structures, also leading to distorted protein dynamics that plausibly affects the function. We hypothesized that missense mutations in cancer-related genes selectively target hinge-neighboring residues that orchestrate collective structural dynamics. To test our hypothesis, we selected 69 cancer-related genes from the Cancer Gene Census database and their representative protein structures from the Protein Data Bank. We first identified the hinge residues in two global modes of motion by applying the Gaussian Network Model. We then showed that missense mutations are significantly enriched on hinge-neighboring residues in oncogenes and tumor suppressor genes. We observed that several oncogenes (eg, MAP2K1, PTPN11, and KRAS) and tumor suppressor genes (eg, EZH2, CDKN2C, and RHOA) strongly exhibit this phenomenon. This study highlights and rationalizes the functional importance of missense mutations on hinge-neighboring residues in cancer.

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Citations

Mar 4, 2020·Proceedings of the National Academy of Sciences of the United States of America·Jose Alberto de la PazFaruck Morcos
Jan 31, 2021·Biophysical Journal·Saliha Ece AcunerTurkan Haliloglu
Apr 30, 2021·The Journal of Physical Chemistry. B·Yiǧit KutluTurkan Haliloglu
Jun 29, 2021·Journal of Molecular Biology·Dana SaadCarlo Camilloni

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