EGFR Juxtamembrane Domain, Membranes, and Calmodulin: Kinetics of Their Interaction

Calcium/calmodulin (Ca/CaM) binds to the intracellular juxtamembrane domain (JMD) of the epidermal growth factor receptor (EGFR). The basic JMD also binds to acidic lipids in the inner leaflet of the plasma membrane, and this interaction may contribute an extra level of autoinhibition to the recepto...

Full description

Saved in:
Bibliographic Details
Published in:Biophysical journal 2009-06, Vol.96 (12), p.4887-4895
Main Authors: Sengupta, Parijat, Bosis, Eran, Nachliel, Esther, Gutman, Menachem, Smith, Steven O., Mihályné, Gyöngyi, Zaitseva, Irina, McLaughlin, Stuart
Format: Article
Language:English
Subjects:
Animals
Binding sites
Biophysics
Calcium
Calmodulin - chemistry
Calmodulin - metabolism
Cattle
Cell Membrane - chemistry
Cell Membrane - metabolism
Diffusion
Kinetics
Lipids
Membrane
Membranes
Peptide Fragments - chemistry
Peptide Fragments - metabolism
Phosphatidylcholines - metabolism
Phosphatidylserines - metabolism
Protein Binding
Reaction kinetics
Receptor, Epidermal Growth Factor - chemistry
Receptor, Epidermal Growth Factor - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Calcium/calmodulin (Ca/CaM) binds to the intracellular juxtamembrane domain (JMD) of the epidermal growth factor receptor (EGFR). The basic JMD also binds to acidic lipids in the inner leaflet of the plasma membrane, and this interaction may contribute an extra level of autoinhibition to the receptor. Binding of a ligand to the EGFR produces a rapid increase in intracellular calcium, [Ca 2+] i, and thus Ca/CaM. How does Ca/CaM compete with the plasma membrane for the JMD? Does Ca/CaM directly pull the JMD off the membrane or does Ca/CaM only bind to the JMD after it has dissociated spontaneously from the bilayer? To answer this question, we studied the effect of Ca/CaM on the rate of dissociation of fluorescent JMD peptides from phospholipid vesicles by making kinetic stop-flow measurements. Ca/CaM increases the rate of dissociation: an analysis of the differential equations that describe the dissociation shows that Ca/CaM must directly pull the basic JMD peptide off the membrane surface. These measurements lead to a detailed atomic-level mechanism for EGFR activation that reconciles the existence of preformed EGFR dimers/oligomers with the Kuriyan allosteric model for activation of the EGFR kinase domains.
ISSN:0006-3495
1542-0086
DOI:10.1016/j.bpj.2009.03.027