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Plexin-Bs enhance their GAP activity with a novel activation switch loop generating a cooperative enzyme.

Cell Mol Life Sci. 2021 Feb;78(3):1101-1112. Epub 2020 Jun 29
Zhen-Lu Li 1 , Jeannine Müller-Greven 1 , SoonJeung Kim 1 , Luca Tamagnone 2 , Matthias Buck 3
Zhen-Lu Li 1 , Jeannine Müller-Greven 1 , SoonJeung Kim 1 , Luca Tamagnone 2 , Matthias Buck 3

[No authors listed]

Author information
  • 1 Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH, 44106, USA.
  • 2 School of Medicine, Università Cattolica del Sacro Cuore, 00168, Rome, Italy.
  • 3 Case Comprehensive Cancer Center, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH, 44106, USA. matthias.buck@case.edu.

摘要


Plexins receive guidance cues from semaphorin ligands and transmit their signal through the plasma membrane. This family of proteins is unique amongst single-pass transmembrane receptors as their intracellular regions interact directly with several small GTPases, which regulate cytoskeletal dynamics and cell adhesion. Here, we characterize the GTPase Activating Protein (GAP) function of Plexin-B1 and find that a cooperative GAP activity towards the substrate GTPase, Rap1b, is associated with the N-terminal Juxtamembrane region of Plexin-B1. Importantly, we unveil an activation mechanism of Plexin-B1 by identifying a novel functional loop which partially blocks Rap1b entry into the plexin GAP domain. Consistent with the concept of allokairy developed for other systems, Plexin-B activity is increased by an apparent substrate-mediated cooperative effect. Simulations and mutagenesis suggest the repositioned JM conformation is stabilized by the new activation switch loop when the active site is occupied, giving rise to faster enzymatic turnover and cooperative behavior. The biological implications, essentially those of a threshold behavior for cell migration, are discussed.

KEYWORDS: Activation threshold, Allostery, Cell migration, Cell signaling, Molecular mechanism, Small GTPases