GTP binding and oncogenic mutations may attenuate hypervariable region (HVR)-catalytic domain interactions in small GTPase K-Ras4B, exposing the effector binding site

Shaoyong Lu, Avik Banerjee, Hyunbum Jang, Jian Zhang*, Vadim Gaponenko, Ruth Nussinov

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

K-Ras4B, a frequently mutated oncogene in cancer, plays an essential role in cell growth, differentiation, and survival. Its C-terminal membrane-associated hypervariable region (HVR) is required for full biological activity. In the active GTP-bound state, the HVR interacts with acidic plasma membrane (PM) headgroups, whereas the farnesyl anchors in the membrane; in the inactive GDP-bound state, the HVR may interact with both the PM and the catalytic domain at the effector binding region, obstructing signaling and nucleotide exchange. Here, using molecular dynamics simulations and NMR, we aim to figure out the effects of nucleotides (GTP and GDP) and frequent (G12C, G12D, G12V, G13D, and Q61H) and infrequent (E37K and R164Q) oncogenic mutations on full-length K-Ras4B. The mutations are away from or directly at the HVR switch I/effector binding site. Our results suggest that full-length wild-type GDP bound K-Ras4B (K-Ras4BWT-GDP) is in an intrinsically auto inhibited state via tight HVR-catalytic domain interactions. The looser association in K-Ras4BWT-GTP may release the HVR. Some of the oncogenic mutations weaken the HVR-catalytic domain association in the K-Ras4B-GDP/-GTP bound states, which may facilitate the HVR dis association in anucleotide-independent manner, thereby up-regulating oncogenic Ras signaling. Thus, our results suggest that mutations can exert their effects in more than one way, abolishing GTP hydrolysis and facilitating effector binding.

Original languageEnglish
Pages (from-to)28887-28900
Number of pages14
JournalJournal of Biological Chemistry
Volume290
Issue number48
DOIs
StatePublished - 27 Nov 2015

Funding

FundersFunder number
American Cancer SocietyRGS-09-057-01-GMC
National Institutes of HealthHHSN261200800001E, R01 CA135341
National Natural Science Foundation of China81473137, 81322046, 81302689
National Cancer InstituteR01CA188427

    Fingerprint

    Dive into the research topics of 'GTP binding and oncogenic mutations may attenuate hypervariable region (HVR)-catalytic domain interactions in small GTPase K-Ras4B, exposing the effector binding site'. Together they form a unique fingerprint.

    Cite this