A molecular basis for integrin αMβ2 ligand binding promiscuity

Valentin P. Yakubenko, Valeryi K. Lishko, Stephen C.T. Lam, Tatiana P. Ugarova

Research output: Contribution to journalArticlepeer-review

102 Scopus citations

Abstract

The leukocyte integrin αMβ2 is a highly promiscuous leukocyte receptor capable of binding a multitude of unrelated ligands. To understand the molecular basis for the broad ligand recognition of αMβ2, the inter-integrin chimera was created. In the chimeric integrin, the βD-α5 loop-α5 helix segment comprised of residues Lys245-Arg261 from the αMI domain of αMβ2 was inserted into the framework of αLβ2. The construct was expressed in HEK 293 cells, and the ability of generated cells to adhere to fibrinogen and its derivatives was characterized first, Grafting the αM(Lys245-Arg261) sequence converted αLβ2 into a fibrinogen-binding protein capable of mediating efficient and specific adhesion similar to that of wild-type αMβ2. Verifying a switch in the binding specificity of αLβ2, the chimeric receptor became competent to support cell migration to fibrinogen. Mutations at positions Phe246, Asp254, and Pro257 within Lys245-Arg261 of αMβ2 produced significant decreases in cell adhesion, illustrating the critical role of these residues in ligand binding. The insertion of αM(Lys245-Arg261) imparted to the chimeric integrin the ability to recognize many typical αMβ2 protein ligands. Furthermore, cells expressing the chimeric receptor, but not αLβ2, were able to stick to uncoated plastic, which represents the hallmark of wild-type αMβ2. These results suggest that αM(Lys245-Arg261) serves as a consensus binding site for interaction with a variety of distinct molecules and, thus, may define the degenerate recognition properties inherent to αMβ2.

Original languageEnglish (US)
Pages (from-to)48635-48642
Number of pages8
JournalJournal of Biological Chemistry
Volume277
Issue number50
DOIs
StatePublished - Dec 13 2002
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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