1. Biochemistry and Chemical Biology
  2. Structural Biology and Molecular Biophysics
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A histidine pH sensor regulates activation of the Ras-specific guanine nucleotide exchange factor RasGRP1

  1. Yvonne Vercoulen
  2. Yasushi Kondo
  3. Jeffrey S Iwig
  4. Alex Janssen
  5. Katharine A White
  6. Mojtaba Amini
  7. Diane L Barber
  8. John Kuriyan  Is a corresponding author
  9. Jeroen P Roose  Is a corresponding author
  1. University of California, San Francisco, United States
  2. University of California, Berkeley, United States
  3. University Medical Center Utrecht, Netherlands
Research Article
  • Cited 12
  • Views 2,484
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Cite this article as: eLife 2017;6:e29002 doi: 10.7554/eLife.29002

Abstract

RasGRPs are guanine nucleotide exchange factors that are specific for Ras or Rap, and are important regulators of cellular signaling. Aberrant expression or mutation of RasGRPs results in disease. An analysis of RasGRP1 SNP variants led to the conclusion that the charge of His 212 in RasGRP1 alters signaling activity and plasma membrane recruitment, indicating that His 212 is a pH sensor that alters the balance between the inactive and active forms of RasGRP1. To understand the structural basis for this effect we compared the structure of autoinhibited RasGRP1, determined previously, to that of active RasGRP4:H-Ras and RasGRP2:Rap1b complexes. The transition from the autoinhibited to the active form of RasGRP1 involves the rearrangement of an inter-domain linker that displaces inhibitory inter-domain interactions. His 212 is located at the fulcrum of these conformational changes, and structural features in its vicinity are consistent with its function as a pH-dependent switch.

Data availability

The following data sets were generated
    1. Kondo
    2. Y.
    3. Iwig
    4. J.S.
    5. Kuriyan
    6. J.
    (2017) Structure of RasGRP2 in complex with Rap1B
    Publicly available at the RCSB Protein Data Bank (Accession no: 6AXF).
    1. Kondo
    2. Y.
    3. Iwig
    4. J.S.
    5. Kuriyan
    6. J.
    (2017) Structure of RasGRP4 in complex with HRas
    Publicly available at the RCSB Protein Data Bank (Accession no: 6AXG).

Article and author information

Author details

  1. Yvonne Vercoulen

    Department of Anatomy, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  2. Yasushi Kondo

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  3. Jeffrey S Iwig

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  4. Alex Janssen

    Department of Anatomy, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  5. Katharine A White

    Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  6. Mojtaba Amini

    Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  7. Diane L Barber

    Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7185-9435
  8. John Kuriyan

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    For correspondence
    jkuriyan@mac.com
    Competing interests
    John Kuriyan, Senior editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4414-5477
  9. Jeroen P Roose

    Department of Anatomy, University of California, San Francisco, San Francisco, United States
    For correspondence
    jeroen.roose@ucsf.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4746-2811

Funding

National Institute of Allergy and Infectious Diseases

  • Jeroen P Roose

National Cancer Institute

  • Katharine A White
  • Diane L Barber

Marie Curie Cancer Care

  • Yvonne Vercoulen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Volker Dötsch, J.W. Goethe-University, Germany

Publication history

  1. Received: May 25, 2017
  2. Accepted: September 5, 2017
  3. Accepted Manuscript published: September 27, 2017 (version 1)
  4. Version of Record published: October 16, 2017 (version 2)

Copyright

© 2017, Vercoulen et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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