The G protein signaling regulator RGS3 enhances the GTPase activity of KRAS Journal Article
| Authors: | Li, C.; Vides, A.; Kim, D.; Xue, J. Y.; Zhao, Y.; Lito, P. |
| Article Title: | The G protein signaling regulator RGS3 enhances the GTPase activity of KRAS |
| Abstract: | Recently reported to be effective in patients with lung cancer, KRASG12C inhibitors bind to the inactive, or guanosine diphosphate (GDP)-bound, state of the oncoprotein and require guanosine triphosphate (GTP) hydrolysis for inhibition. However, KRAS mutations prevent the catalytic arginine of GTPase-activating proteins (GAPs) from enhancing an otherwise slow hydrolysis rate. If KRAS mutants are indeed insensitive to GAPs, it is unclear how KRASG12C hydrolyzes sufficient GTP to allow inactive state-selective inhibition. Here, we show that RGS3, a GAP previously known for regulating G protein-coupled receptors, can also enhance the GTPase activity of mutant and wild-type KRAS proteins. Our study reveals an unexpected mechanism that inactivates KRAS and explains the vulnerability to emerging clinically effective therapeutics. © 2021 American Association for the Advancement of Science. All rights reserved. |
| Keywords: | mutation; protein; enzyme activity; inhibitor; hydrolysis; inhibition |
| Journal Title: | Science |
| Volume: | 374 |
| Issue: | 6564 |
| ISSN: | 0036-8075 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2021-10-08 |
| Start Page: | abf1730 |
| Language: | English |
| DOI: | 10.1126/science.abf1730 |
| PROVIDER: | scopus |
| PUBMED: | 34618566 |
| PMCID: | PMC9295010 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 November 2021 -- Source: Scopus |
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