High-Affinity Bent β2-Integrin Molecules in Arresting Neutrophils Face Each Other through Binding to ICAMs In cis

Zhichao Fan, William Bill Kiosses, Hao Sun, Marco Orecchioni, Yanal Ghosheh, Dirk M. Zajonc, M. Amin Arnaout, Edgar Gutierrez, Alex Groisman, Mark H. Ginsberg, Klaus Ley

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

Leukocyte adhesion requires β2-integrin activation. Resting integrins exist in a bent-closed conformation—i.e., not extended (E) and not high affinity (H)—unable to bind ligand. Fully activated E+H+ integrin binds intercellular adhesion molecules (ICAMs) expressed on the opposing cell in trans. EH transitions to E+H+ through E+H or through EH+, which binds to ICAMs on the same cell in cis. Spatial patterning of activated integrins is thought to be required for effective arrest, but no high-resolution cell surface localization maps of activated integrins exist. Here, we developed Super-STORM by combining super-resolution microscopy with molecular modeling to precisely localize activated integrin molecules and identify the molecular patterns of activated integrins on primary human neutrophils. At the time of neutrophil arrest, EH+ integrins face each other to form oriented (non-random) nanoclusters. To address the mechanism causing this pattern, we blocked integrin binding to ICAMs in cis, which significantly relieved the face-to-face orientation.

Original languageEnglish (US)
Pages (from-to)119-130.e5
JournalCell Reports
Volume26
Issue number1
DOIs
StatePublished - Jan 2 2019
Externally publishedYes

Keywords

  • STORM
  • TIRF
  • human
  • integrin
  • integrin activation
  • molecular modeling
  • neutrophil
  • superresolution

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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