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Coaction of Electrostatic and Hydrophobic Interactions: Dynamic Structural Constraints on Disordered TrkA Juxtamembrane Domain

preprint
submitted on 16.09.2019 and posted on 20.09.2019 by Zichen Wang, Huaxun Fan, Xiao Hu, John Khamo, Jiajie Diao, Kai Zhang, Taras Pogorelov

Effective transmembrane signaling is vital to the life of the cell. However, plasma membrane dynamics pose numerous challenges for signaling proteins and attempts to study them. The receptor tyrosine kinase family transmits signals via a single transmembrane helix and a flexible juxtamembrane domain (JMD). Detailed
studies of JMD-membrane interactions are challenging due to naturally slow lipid diffusion. We employ a combination of all-atom molecular dynamics of highly mobile membrane mimetics with in vitro and in cell experiments to capture critical roles of electrostatic and hydrophobic membrane-JMD interactions of
tropomyosin receptor kinase A (TrkA). We show that a conserved three-residue hydrophobic patch enables JMD anchoring in the membrane, a single residue deletion can dramatically reverse it, and a single charged to hydrophobic residue mutation can enhance binding affinity. The highly charged anionic lipids are effective
at promoting binding and restraining JMD flexibility. Our work highlights versatility of molecular controls of these interactions.

History

Email Address of Submitting Author

pogorelo@illinois.edu

Institution

University of Illinois at Urbana-Champaign

Country

USA

ORCID For Submitting Author

0000-0001-5851-7721

Declaration of Conflict of Interest

None

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