Myr-Arf1 conformational flexibility at the membrane surface sheds light on the interactions with ArfGAP ASAP1

Yue Zhang, Olivier Soubias, Shashank Pant, Frank Heinrich, Alexander Vogel, Jess Li, Yifei Li, Luke A. Clifton, Sebastian Daum, Kirsten Bacia, Daniel Huster, Paul A. Randazzo, Mathias Lösche, Emad Tajkhorshid and R. Andrew Byrd ()
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Yue Zhang: National Cancer Institute
Olivier Soubias: National Cancer Institute
Shashank Pant: University of Illinois at Urbana-Champaign
Frank Heinrich: Department of Physics, Carnegie Mellon University
Alexander Vogel: University of Leipzig
Jess Li: National Cancer Institute
Yifei Li: National Cancer Institute
Luke A. Clifton: Rutherford Appleton Laboratory
Sebastian Daum: Martin Luther University Halle-Wittenberg
Kirsten Bacia: Martin Luther University Halle-Wittenberg
Daniel Huster: University of Leipzig
Paul A. Randazzo: National Institutes of Health
Mathias Lösche: Department of Physics, Carnegie Mellon University
Emad Tajkhorshid: University of Illinois at Urbana-Champaign
R. Andrew Byrd: National Cancer Institute

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract ADP-ribosylation factor 1 (Arf1) interacts with multiple cellular partners and membranes to regulate intracellular traffic, organelle structure and actin dynamics. Defining the dynamic conformational landscape of Arf1 in its active form, when bound to the membrane, is of high functional relevance and key to understanding how Arf1 can alter diverse cellular processes. Through concerted application of nuclear magnetic resonance (NMR), neutron reflectometry (NR) and molecular dynamics (MD) simulations, we show that, while Arf1 is anchored to the membrane through its N-terminal myristoylated amphipathic helix, the G domain explores a large conformational space, existing in a dynamic equilibrium between membrane-associated and membrane-distal conformations. These configurational dynamics expose different interfaces for interaction with effectors. Interaction with the Pleckstrin homology domain of ASAP1, an Arf-GTPase activating protein (ArfGAP), restricts motions of the G domain to lock it in what seems to be a conformation exposing functionally relevant regions.

Date: 2023
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DOI: 10.1038/s41467-023-43008-5

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