Structural Characterization of the Interaction between the αmI-Domain of the Integrin Mac-1 (αMβ2) and the Cytokine Pleiotrophin

Wei Feng, Hoa Nguyen, Di Shen, Hanqing Deng, Zhoumai Jiang, Nataly Podolnikova, Tatiana Ugarova, Xu Wang

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Integrin Mac-1 (αMβ2) is an adhesion receptor vital to many functions of myeloid leukocytes. It is also the most promiscuous member of the integrin family capable of recognizing a broad range of ligands. In particular, its ligand-binding αMI-domain is known to bind cationic proteins/peptides depleted in acidic residues. This contradicts the canonical ligand-binding mechanism of αI-domains, which requires an acidic amino acid in the ligand to coordinate the divalent cation within the metal ion-dependent adhesion site (MIDAS) of αI-domains. The lack of acidic amino acids in the αMI-domain-binding sequences suggests the existence of an as-yet uncharacterized interaction mechanism. In the present study, we analyzed interactions of the αMI-domain with a representative Mac-1 ligand, the cationic cytokine pleiotrophin (PTN). Through NMR chemical shift perturbation analysis, cross saturation, NOESY, and mutagenesis studies, we found the interaction between the αMI-domain and PTN is divalent cation-independent and mediated mostly by hydrophobic contacts between the N-terminal domain of PTN and residues in the α5-β5 loop of αMI-domain. The observation that increased ionic strength weakens the interaction between the proteins indicates electrostatic forces may also play a significant role in the binding. On the basis of the results from these experiments, we formulated a model of the interaction between the αMI-domain and PTN.

Original languageEnglish (US)
Pages (from-to)182-193
Number of pages12
JournalBiochemistry
Volume60
Issue number3
DOIs
StatePublished - Jan 26 2021

ASJC Scopus subject areas

  • Biochemistry

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