The Structural Basis of the Farnesylated and Methylated KRas4B Interaction with Calmodulin

Hyunbum Jang, Avik Banerjee, Kendra Marcus, Lee Makowski, Carla Mattos, Vadim Gaponenko, Ruth Nussinov*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Ca2+-calmodulin (CaM) extracts KRas4B from the plasma membrane, suggesting that KRas4B/CaM interaction plays a role in regulating Ras signaling. To gain mechanistic insight, we provide a computational model, supported by experimental structural data, of farnesylated/methylated KRas4B1-185 interacting with CaM in solution and at anionic membranes including signaling lipids. Due to multiple interaction modes, we observe diverse conformational ensembles of the KRas4B-CaM complex. A highly populated conformation reveals the catalytic domain interacting with the N-lobe and the hypervariable region (HVR) wrapping around the linker with the farnesyl docking to the extended CaM's C-lobe pocket. Alternatively, KRas4B can interact with collapsed CaM with the farnesyl penetrating CaM's center. At anionic membranes, CaM interacts with the catalytic domain with large fluctuations, drawing the HVR. Signaling lipids establishing strong salt bridges with CaM prevent membrane departure. Membrane-interacting KRas4B-CaM complex can productively recruit phosphatidylinositol 3-kinase α (PI3Kα) to the plasma membrane, serving as a coagent in activating PI3Kα/Akt signaling.

Original languageEnglish
Pages (from-to)1647-1659.e4
JournalStructure
Volume27
Issue number11
DOIs
StatePublished - 5 Nov 2019

Funding

FundersFunder number
NCI Ras initiative
L.M.
Department of Health, Australian Government
NSF and NIH/National Institute of General Medical Sciences
National Institutes of Health
Horizon Award fellowship
US government
Horizon Award
Macromolecular X-ray science
Intramural Research Program
Cornell High Energy Synchrotron Source
National Cancer InstituteHHSN26120080001E
NIH/NIGMSGM-103485
Congressionally Directed Medical Research ProgramsW81XWH-17-1-0509
National Institute of General Medical SciencesDMR-1332208
National Science Foundation1332208, MCB-1517295
Center for Cancer ResearchR01 5R01CA188427-04
U.S. Department of DefenseDefense

    Keywords

    • KRAS
    • MD simulation
    • NMR
    • PI3K
    • PIP
    • SAXS
    • farnesylation and methylation
    • hypervariable region
    • phosphatidylinositol
    • post-translational modifications

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