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

59 Pages Posted: 11 Jul 2019 Sneak Peek Status: Published

See all articles by Hyunbum Jang

Hyunbum Jang

National Laboratory for Cancer Research

Avik Banerjee

University of Illinois at Chicago

Kendra Marcus

Northeastern University

Lee Makowski

Northeastern University

Carla Mattos

Northeastern University - Department of Chemistry and Chemical Biology

Vadim Gaponenko

University of Illinois at Chicago

Ruth Nussinov

National Institutes of Health (NIH) - National Cancer Institute at Frederick ; Tel Aviv University - Department of Human Molecular Genetics and Biochemistry

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Abstract

Ca2+-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-GTP 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 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 that draw the HVR. Signaling lipids establishing strong salt bridges with CaM can prevent membrane departure. Membrane-interacting KRas4B–CaM complex can productively recruit PI3Kα to the plasma membrane, serving as a coagent in activating PI3Kα/Akt signaling.

Keywords: post-translational modifications, farnesylation and methylation, phosphatidylinositol, PIP2, NMR, MD simulation, SAXS, PI3K

Suggested Citation

Jang, Hyunbum and Banerjee, Avik and Marcus, Kendra and Makowski, Lee and Mattos, Carla and Gaponenko, Vadim and Nussinov, Ruth, The Structural Basis of the Farnesylated and Methylated KRas4B Interaction with Calmodulin (July 11, 2019). STRUCTURE-D-19-00185. Available at SSRN: https://ssrn.com/abstract=3417943 or http://dx.doi.org/10.2139/ssrn.3417943
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Hyunbum Jang

National Laboratory for Cancer Research ( email )

United States

Avik Banerjee

University of Illinois at Chicago

Kendra Marcus

Northeastern University

220 B RP
Boston, MA 02115
United States

Lee Makowski

Northeastern University

220 B RP
Boston, MA 02115
United States

Carla Mattos

Northeastern University - Department of Chemistry and Chemical Biology ( email )

Boston, MA 02115
United States

Vadim Gaponenko

University of Illinois at Chicago

1200 W Harrison St
Chicago, IL 60607
United States

Ruth Nussinov (Contact Author)

National Institutes of Health (NIH) - National Cancer Institute at Frederick

Frederick, MD 21702-1201
United States

Tel Aviv University - Department of Human Molecular Genetics and Biochemistry

Tel Aviv, 69978
Israel

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