Coaction of Electrostatic an Hyrophobic Interactions: Dynamic Constraints on Disorere TrkA Juxtamembrane Domain

Zichen Wang, Huaxun Fan, Xiao Hu, John Khamo, Jiajie Diao, Kai Zhang, Taras V. Pogorelov

Research output: Contribution to journalArticle

Abstract

In the receptor tyrosine kinase family, conformational change inuce by ligan bining is transmitte across the membrane via a single transmembrane helix an a flexible juxtamembrane omain (JMD). Membrane ynamics makes it challenging to stuy the structural mechanism of receptor activation experimentally. In this stuy, we employ all-atom molecular ynamics with highly mobile membrane mimetic (HMMM) to capture the native conformation of the JMD in tropomyosin receptor kinase A (TrkA). We fin that phosphatiylinositol 4,5-bisphosphate (PIP2) lipis engage in stable bining with multiple basic resiues. Anionic lipis can compete with salt briges within the peptie an alter TrkA-JMD conformation. We iscover three-resiue insertion into the membrane an are able to either enhance or reuce the level of insertion through computationally-esigne point mutations. The vesicle-bining experiment supports computational results an inicates that hyrophobic insertion is comparable to electrostatic bining for membrane anchoring. Biochemical assays on cell lines with mutate TrkA show that enhance TrkA-JMD insertion promotes receptor egraation but oes not affect the short-term signaling capacity. Our joint work points to a scenario where lipi heagroups an tails interact with basic an hyrophobic resiues on isorere omain, respectively, to restrain flexibility an potentially moulate protein function.

Original languageEnglish (US)
Pages (from-to)10709-10717
Number of pages9
JournalJournal of Physical Chemistry B
Volume123
Issue number50
DOIs
StatePublished - Dec 19 2019

Fingerprint

Tropomyosin
Electrostatics
Phosphotransferases
electrostatics
Membranes
insertion
membranes
clopidogrel
interactions
Conformations
Receptor Protein-Tyrosine Kinases
Assays
tyrosine
Salts
fins
Chemical activation
mutations
Cells
cultured cells
helices

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry

Cite this

Coaction of Electrostatic an Hyrophobic Interactions : Dynamic Constraints on Disorere TrkA Juxtamembrane Domain. / Wang, Zichen; Fan, Huaxun; Hu, Xiao; Khamo, John; Diao, Jiajie; Zhang, Kai; Pogorelov, Taras V.

In: Journal of Physical Chemistry B, Vol. 123, No. 50, 19.12.2019, p. 10709-10717.

Research output: Contribution to journalArticle

Wang, Zichen ; Fan, Huaxun ; Hu, Xiao ; Khamo, John ; Diao, Jiajie ; Zhang, Kai ; Pogorelov, Taras V. / Coaction of Electrostatic an Hyrophobic Interactions : Dynamic Constraints on Disorere TrkA Juxtamembrane Domain. In: Journal of Physical Chemistry B. 2019 ; Vol. 123, No. 50. pp. 10709-10717.
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