Ligand and cation-induced structural alterations of the leukocyte integrin LFA-1

Citation:

Sen, M., Koksal, A.C., Yuki, K., Wang, J. & Springer, T.A. Ligand and cation-induced structural alterations of the leukocyte integrin LFA-1. J Biol Chem (2018).
Ligand and cation-induced structural alterations of the leukocyte integrin LFA-1

Date Published:

2018 Mar 05

Abstract:

In αI integrins including leukocyte function-associated antigen-1 (LFA-1), ligand-binding function is delegated to the αI domain, requiring extra steps in the relay of signals that activate ligand binding and coordinate it with cytoplasmic signals. Crystal structures reveal great variation in orientation between the αI domain and the remainder of the integrin head. Here, we investigated the mechanisms involved in signal relay to the αI domain, including whether binding of the ligand intercellular adhesion molecule-1 (ICAM-1) to the αI domain is linked to headpiece opening and engenders a preferred αI domain orientation. Using small-angle X-ray scattering (SAXS) and negative-stain EM we define structures of ICAM-1, LFA-1, and their complex, and the effect of activation by Mn Headpiece opening was substantially stabilized by substitution of Mg with Mn and became complete upon ICAM-1 addition. These agents stabilized αI-headpiece orientation, resulting in a well-defined orientation of ICAM-1 such that its tandem Ig-like domains pointed in the opposite direction from the β-subunit leg of LFA-1. Mutations in the integrin βI domain α1/α1` helix stabilizing either the open or the closed βI-domain conformation indicated that α1/α1` helix movements are linked to ICAM-1 binding by the αI domain and to the extended-open conformation of the ectodomain. The LFA-1--ICAM-1 orientation described here with ICAM-1 pointing anti-parallel to the LFA-1 β-subunit leg is the same orientation that would be stabilized by tensile force transmitted between the ligand and the actin cytoskeleton, and is consistent with the cytoskeletal force model of integrin activation.

Last updated on 04/24/2018