title: Reversible - through calmodulin - electrostatic interactions between basic residues on proteins and acidic lipids in the plasma membrane.
abstract: The inner leaflet of a typical mammalian plasma membrane contains 20-30% univalent PS (phosphatidylserine) and 1% multivalent PtdIns(4,5)P(2). Numerous proteins have clusters of basic (or basic/hydrophobic) residues that bind to these acidic lipids. The intracellular effector CaM (calmodulin) can reverse this binding on a wide variety of proteins, including MARCKS (myristoylated alanine-rich C kinase substrate), GAP43 (growth-associated protein 43, also known as neuromodulin), gravin, GRK5 (G-protein-coupled receptor kinase 5), the NMDA (N-methyl-D-aspartate) receptor and the ErbB family. We used the first principles of physics, incorporating atomic models and the Poisson-Boltzmann equation, to describe how the basic effector domain of MARCKS binds electrostatically to acidic lipids on the plasma membrane. The theoretical calculations show the basic cluster produces a local positive electrostatic potential that should laterally sequester PtdIns(4,5)P(2), even when univalent acidic lipids are present at a physiologically relevant 100-fold excess; four independent experimental measurements confirm this prediction. Ca(2+)/CaM binds with high affinity (K(d) approximately 10nM) to this domain and releases the PtdIns(4,5)P(2). MARCKS, a major PKC (protein kinase C) substrate, is present at concentrations comparable with those of PtdIns(4,5)P(2) (approx. 10 microM) in many cell types. Thus MARCKS can act as a reversible PtdIns(4,5)P(2) buffer, binding PtdIns(4,5)P(2) in a quiescent cell, and releasing it locally when the intracellular Ca(2+) concentration increases. This reversible sequestration is important because PtdIns(4,5)P(2) plays many roles in cell biology. Less is known about the role of CaM-mediated reversible membrane binding of basic/hydrophobic clusters for the other proteins.
authors.affiliation: Department of Physiology and Biophysics, Health Science Center, SUNY Stony Brook, New York, NY 11794, U.S.A. smcl@epo.som.sunysb.edu
authors.forename: Stuart
authors.initials: S
authors.lastname: McLaughlin
authors.forename: Gyöngyi
authors.initials: G
authors.lastname: Hangyás-Mihályné
authors.forename: Irina
authors.initials: I
authors.lastname: Zaitseva
authors.forename: Urszula
authors.initials: U
authors.lastname: Golebiewska
mesh_terms: D000818:Animals; D002147:Calmodulin / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism; D008563:Membrane Lipids / Q000737:chemistry* / Q000378:metabolism*; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism*; D008954:Models, Biological; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D055672:Static Electricity
chemical_list: D002147:Calmodulin; D047908:Intracellular Signaling Peptides and Proteins; C000619710:MARCKS protein, human; D008563:Membrane Lipids; D008565:Membrane Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D000076250:Myristoylated Alanine-Rich C Kinase Substrate