Open Collections

Holguín Cruz, Jorge Andrés

University of British Columbia

Autoinhibition is a prevalent allosteric regulatory mechanism in signaling proteins that prevents spurious pathway activation and primes for signal propagation only under appropriate inputs. Altered functioning of inhibitory allosteric switches underlies the tumorigenic effect of some known cancer drivers. Whether there is a widespread alteration of protein autoinhibition in cancer remains elusive. Here, we demonstrate that cancer-associated missense mutations, in-frame insertions/deletions as well as fusion breakpoints are significantly enriched within inhibitory allosteric switches across many cancer types. Selection for inhibitory allosteric switches that are recurrently mutated in cancers identifies established as well as putative new cancer drivers. Importantly, recurrent missense mutations in inhibitory allosteric switches of these drivers are associated with distinct, cancer-specific changes in molecular signaling. For the specific case of PPP3CA, the catalytic subunit of the calcineurin phosphatase, we provide insights into the potential molecular mechanisms of altered autoinhibition by cancer mutations using biomolecular simulations and demonstrate that such mutations are associated with transcriptome changes consistent with increased calcineurin signaling. Our integrative study shows that autoinhibition-modulating genetic alterations are positively selected for by cancer cells, and that their investigation provides valuable insights into the molecular mechanisms of cancer.

Text; Dataset

2024-11-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/85467

Bioinformatics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/