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Residues within a lipid-associated segment of the PECAM-1 cytoplasmic domain are susceptible to inducible, sequential phosphorylation. Blood 2011 Jun 02;117(22):6012-23

Date

04/06/2011

Pubmed ID

21464369

Pubmed Central ID

PMC3112045

DOI

10.1182/blood-2010-11-317867

Scopus ID

2-s2.0-79958011812   25 Citations

Abstract

Immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptors inhibit cellular responsiveness to immunoreceptor tyrosine-based activation motif (ITAM)-linked receptors. Although tyrosine phosphorylation is central to the initiation of both inhibitory ITIM and stimulatory ITAM signaling, the events that regulate receptor phosphorylation are incompletely understood. Previous studies have shown that ITAM tyrosines engage in structure-inducing interactions with the plasma membrane that must be relieved for phosphorylation to occur. Whether ITIM phosphorylation is similarly regulated and the mechanisms responsible for release from plasma membrane interactions to enable phosphorylation, however, have not been defined. PECAM-1 is a dual ITIM-containing receptor that inhibits ITAM-dependent responses in hematopoietic cells. We found that the PECAM-1 cytoplasmic domain is unstructured in an aqueous environment but adopts an α-helical conformation within a localized region on interaction with lipid vesicles that mimic the plasma membrane. The lipid-interacting segment contains the C-terminal ITIM tyrosine and a serine residue that undergo activation-dependent phosphorylation. The N-terminal ITIM is excluded from the lipid-interacting segment, and its phosphorylation is secondary to phosphorylation of the membrane-interacting C-terminal ITIM. On the basis of these findings, we propose a novel model for regulation of inhibitory signaling by ITIM-containing receptors that relies on reversible plasma membrane interactions and sequential ITIM phosphorylation.

Author List

Paddock C, Lytle BL, Peterson FC, Holyst T, Newman PJ, Volkman BF, Newman DK

Authors

Debra K. Newman PhD Investigator in the Blood Research Institute department at BloodCenter of Wisconsin
Debra K. Newman PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Peter J. Newman PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Francis C. Peterson PhD Professor in the Biochemistry department at Medical College of Wisconsin
Brian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Cell Membrane
Circular Dichroism
Cytoplasm
Humans
Micelles
Peptide Fragments
Phosphorylation
Phosphorylcholine
Phosphotyrosine
Platelet Activation
Platelet Aggregation
Platelet Endothelial Cell Adhesion Molecule-1
Recombinant Proteins
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
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