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J. Biol. Chem., Vol. 278, Issue 24, 21459-21466, June 13, 2003

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Binding of Peptides with Basic and Aromatic Residues to Bilayer Membranes

PHENYLALANINE IN THE MYRISTOYLATED ALANINE-RICH C KINASE SUBSTRATE EFFECTOR DOMAIN PENETRATES INTO THE HYDROPHOBIC CORE OF THE BILAYER^*

Wenyi Zhang , Evan Crocker , Stuart McLaughlin ¶ and Steven O. Smith  ||

From the Department of Biochemistry and Cell Biology, Center for Structural Biology, State University of New York, Stony Brook, New York 11794-5115, Department of Physics and Astronomy, Center for Structural Biology, State University of New York, Stony Brook, New York 11794-5115, ^¶ Department of Physiology and Biophysics, Center for Structural Biology, State University of New York, Stony Brook, New York 11794-5115

Electrostatic interactions with positively charged regions of membrane-associated proteins such as myristoylated alanine-rich C kinase substrate (MARCKS) may have a role in regulating the level of free phosphatidylinositol 4,5-bisphosphate (PI(4,5)P₂) in plasma membranes. Both the MARCKS protein and a peptide corresponding to the effector domain (an unstructured region that contains 13 basic residues and 5 phenylalanines), MARCKS-(151–175), laterally sequester the polyvalent lipid PI(4,5)P₂ in the plane of a bilayer membrane with high affinity. We used high resolution magic angle spinning NMR to establish the location of MARCKS-(151–175) in membrane bilayers, which is necessary to understand the sequestration mechanism. Measurements of cross-relaxation rates in two-dimensional nuclear Overhauser enhancement spectroscopy NMR experiments show that the five Phe rings of MARCKS-(151–175) penetrate into the acyl chain region of phosphatidylcholine bilayers containing phosphatidylglycerol or PI(4,5)P₂. Specifically, we observed strong cross-peaks between the aromatic protons of the Phe rings and the acyl chain protons of the lipids, even for very short (50 ms) mixing times. The position of the Phe rings implies that the adjacent positively charged amino acids in the peptide are close to the level of the negatively charged lipid phosphates. The deep location of the MARCKS peptide in the polar head group region should enhance its electrostatic sequestration of PI(4,5)P₂ by an "image charge" mechanism. Moreover, this location has interesting implications for membrane curvature and local surface pressure effects and may be relevant to a wide variety of other proteins with basic-aromatic clusters, such as phospholipase D, GAP43, SCAMP2, and the N-methyl-D-aspartate receptor.

Received for publication, February 17, 2003 , and in revised form, March 31, 2003.

^* This work was supported by National Institutes of Health Grants GM46732 (to S. O. S.) and GM24971 (to S. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Biochemistry and Cell Biology, Center for Structural Biology, 450 Life Sciences Bldg., Z-5115, SUNY, Stony Brook, NY 11794-5115. Tel.: 631-632-1210; Fax: 631-632-8575; E-mail: steven.o.smith{at}sunysb.edu.

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