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

  1. Author:
    Jang,Hyunbum
    Banerjee, Avik
    Marcus, Kendra
    Makowski, Lee
    Mattos, Carla
    Gaponenko, Vadim
    Nussinov,Ruth

  2. Author Address

    Computational Structural Biology Section, Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA., Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA., Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA., Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA., Computational Structural Biology Section, Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: nussinor@mail.nih.gov.,
    1. Year: 2019
    2. Date: Nov 5
    3. Epub Date: 2019 09 04
  2. Journal: Structure (London, England : 1993)
    1. 27
    2. 11
    3. Pages: 1647-1659.e4
  4. Type of Article: Article
  5. ISSN: 0969-2126
  1. 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 a (PI3Ka) to the plasma membrane, serving as a coagent in activating PI3Ka/Akt signaling. Copyright © 2019 Elsevier Ltd. All rights reserved.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.str.2019.08.009
  3. PMID: 31495533
  4. View record in Web of Science®
  5. WOS: 000494979900006
  6. PII : S0969-2126(19)30280-1

Library Notes

  1. Fiscal Year: FY2019-2020
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