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Membrane surface recognition by the ASAP1 PH domain and consequences for interactions with the small GTPase Arf1

  1. Author:
    Soubias, Olivier [ORCID]
    Pant, Shashank
    Heinrich, Frank [ORCID]
    Zhang,Yue [ORCID]
    Roy, Neeladri Sekhar
    Li,Jess [ORCID]
    Jian, Xiaoying
    Yohe, Marielle E [ORCID]
    Randazzo, Paul A [ORCID]
    Lösche, Mathias [ORCID]
    Tajkhorshid, Emad [ORCID]
    Byrd,Robert [ORCID]

  2. Author Address

    Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702-1201, USA., NIH Center for Macromolecular Modeling and Bioinformatics, Beckman Institute for Advanced Science and Technology, Department of Biochemistry, Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA., Department of Physics, Carnegie Mellon University, Pittsburgh, PA 15213, USA., NIST Center for Neutron Research, Gaithersburg, MD 20878, USA., Laboratory of Cellular and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Department of Physics, Carnegie Mellon University, Pittsburgh, PA 15213, USA. loesche@andrew.cmu.edu emad@life.illinois.edu byrdra@mail.nih.gov., Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA., NIH Center for Macromolecular Modeling and Bioinformatics, Beckman Institute for Advanced Science and Technology, Department of Biochemistry, Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. loesche@andrew.cmu.edu emad@life.illinois.edu byrdra@mail.nih.gov., Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702-1201, USA. loesche@andrew.cmu.edu emad@life.illinois.edu byrdra@mail.nih.gov.,
    1. Year: 2020
    2. Date: Sep
    3. Epub Date: 2020 09 30
  2. Journal: Science advances
    1. 6
    2. 40
    3. Pages: pii: eabd1882
  4. Type of Article: Article
  5. Article Number: eabd1882
  6. ISSN: 2375-2548
  1. Abstract:

    Adenosine diphosphate-ribosylation factor (Arf) guanosine triphosphatase-activating proteins (GAPs) are enzymes that need to bind to membranes to catalyze the hydrolysis of guanosine triphosphate (GTP) bound to the small GTP-binding protein Arf. Binding of the pleckstrin homology (PH) domain of the ArfGAP With SH3 domain, ankyrin repeat and PH domain 1 (ASAP1) to membranes containing phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] is key for maximum GTP hydrolysis but not fully understood. By combining nuclear magnetic resonance, neutron reflectometry, and molecular dynamics simulation, we show that binding of multiple PI(4,5)P2 molecules to the ASAP1 PH domain (i) triggers a functionally relevant allosteric conformational switch and (ii) maintains the PH domain in a well-defined orientation, allowing critical contacts with an Arf1 mimic to occur. Our model provides a framework to understand how binding of the ASAP1 PH domain to PI(4,5)P2 at the membrane may play a role in the regulation of ASAP1. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

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External Sources

  1. View Full Text
  2. DOI: 10.1126/sciadv.abd1882
  3. PMID: 32998886
  4. View record in Web of Science®
  5. WOS: 000579157800041
  6. PII : 6/40/eabd1882

Library Notes

  1. Fiscal Year: FY2020-2021
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