The Journal of General Physiology
Avanti Polar Lipids
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Published online 13 June 2005 doi:10.1085/jgp.200509274
The Rockefeller University Press, 0022-1295 $8.00
JGP, Volume 126, Number 1, 41-53
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ARTICLE

 An Electrostatic Engine Model for Autoinhibition and Activation of the Epidermal Growth Factor Receptor (EGFR/ErbB) Family

Stuart McLaughlin1, Steven O. Smith2, Michael J. Hayman3, and Diana Murray4

1 Department of Physiology and Biophysics, HSC
2 Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794
3 Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794
4 Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021

Address correspondence to Stuart McLaughlin: Stuart.McLaughlin{at}StonyBrook.edu

We propose a new mechanism to explain autoinhibition of the epidermal growth factor receptor (EGFR/ErbB) family of receptor tyrosine kinases based on a structural model that postulates both their juxtamembrane and protein tyrosine kinase domains bind electrostatically to acidic lipids in the plasma membrane, restricting access of the kinase domain to substrate tyrosines. Ligand-induced dimerization promotes partial trans autophosphorylation of ErbB1, leading to a rapid rise in intracellular [Ca2+] that can activate calmodulin. We postulate the Ca2+/calmodulin complex binds rapidly to residues 645–660 of the juxtamembrane domain, reversing its net charge from +8 to –8 and repelling it from the negatively charged inner leaflet of the membrane. The repulsion has two consequences: it releases electrostatically sequestered phosphatidylinositol 4,5-bisphosphate (PIP2), and it disengages the kinase domain from the membrane, allowing it to become fully active and phosphorylate an adjacent ErbB molecule or other substrate. We tested various aspects of the model by measuring ErbB juxtamembrane peptide binding to phospholipid vesicles using both a centrifugation assay and fluorescence correlation spectroscopy; analyzing the kinetics of interactions between ErbB peptides, membranes, and Ca2+/calmodulin using fluorescence stop flow; assessing ErbB1 activation in Cos1 cells; measuring fluorescence resonance energy transfer between ErbB peptides and PIP2; and making theoretical electrostatic calculations on atomic models of membranes and ErbB juxtamembrane and kinase domains.

Abbreviations used in this paper: Ca/CaM, calcium/calmodulin; CD, circular dichroism; EGFR, epidermal growth factor receptor; FCS, fluorescence correlation spectroscopy; FRET, fluorescence resonance energy transfer; IP3, inositiol 1,4,5-trisphosphate; JM, juxtamembrane; LUV, large unilamellar vesicle; MLV, multilamellar vesicle; NEM, [ethyl-1,2-3H]N-ethylmaleimide; PC, phosphatidylcholine; PIP2, phosphatidylinositol 4,5-bisphosphate; PS, phosphatidylserine; PTK, protein tyrosine kinase; TM, transmembrane.


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