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High Affinity Bent β 2 Integrin Binds Ligand in Cis and Regulates Inflammation
Author(s) -
Fan Zhichao,
McArdle Sara,
Mikulski Zbigniew,
Gutierrez Edgar,
Ginsberg Mark,
Groisman Alex,
Ley Klaus
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1210.2
Subject(s) - integrin , microbiology and biotechnology , ligand (biochemistry) , chemistry , adhesion , cell adhesion , förster resonance energy transfer , biophysics , cell adhesion molecule , integrin, beta 6 , biology , cell , biochemistry , receptor , physics , organic chemistry , quantum mechanics , fluorescence
Integrins are bidirectional signaling molecules that are bent at rest. Upon cell activation, integrins can extend (E + ) and acquire a high affinity conformation with an “open” headpiece (H + ). The canonical “switchblade” model of integrin activation proposes that the E + conformation precedes H + , and the two are thought to be structurally linked. Only the E + H + conformation can mediate cell adhesion by binding to ligand in trans. Here, by using high‐resolution quantitative dynamic footprinting (qDF) microscopy combined with a homogenous conformation‐reporter binding assay, we show that a substantial fraction of β 2 integrins on human neutrophils acquires an unexpected E − H + conformation not previously seen on primary cells. We show that E − H + integrin is functional because it binds its ligand intercellular adhesion molecule 1 (ICAM‐1) in cis and significantly inhibits neutrophil adhesion under flow, which is demonstrated by Förster resonance energy transfer assay, qDF imaging and microfluidic neutrophil adhesion assay and intravital cremaster imaging on neutrophil adaptive transfered mice. These findings suggest that integrin extension does not necessarily precede high affinity and the two are regulated independently. Support or Funding Information NIH funding HL078784