Structures of the αL I Domain and Its Complex with ICAM-1 Reveal a Shape-Shifting Pathway for Integrin Regulation

Abstract

The structure of the I domain of integrin alpha L beta 2 bound to the Ig superfamily ligand ICAM-1 reveals the open ligand binding conformation and the first example of an integrin-IgSF interface. The I domain Mg2+ directly coordinates Glu-34 of ICAM-1, and a dramatic swing of I domain residue Glu-241 enables a critical salt bridge. Liganded and unliganded structures for both high- and intermediate-affinity mutant I domains reveal that ligand binding can induce conformational change in the alpha L I domain and that allosteric signals can convert the closed conformation to intermediate or open conformations without ligand binding. Pulling down on the C-terminal alpha 7 helix with introduced disulfide bonds ratchets the beta 6-alpha 7 loop into three different positions in the closed, intermediate, and open conformations, with a progressive increase in affinity.

Role of the αI domain in ligand binding by integrin αEβ7

“…Crystal structures are now known for the I domains of integrin § chains § 1, § 2, § L, § M and § X [1][2][3][4][5][6] and for § 2 and § L in complex with their respective ligands, collagen and ICAM-1 [7,8]. These structures have provided persuasive evidence that § I domains undergo a major conformational change associated with ligand binding by the metal ion-dependent adhesion site (MIDAS).…”

Structural and mechanical functions of integrins

“…extended with a closed headpiece (high affinity); (3) ligand occupied, i.e. extended with an open headpiece (Xiong et al 2001(Xiong et al , 2002Shimaoka et al 2003;Xiao et al 2004). At the present time, two models are proposed to describe the process of integrin activation: the 'deadbolt' model and the 'switchblade' model (Xiong et al 2003;Luo et al 2007).…”

“…To overcome this physical barrier, the application of force is required to compress the glycocalyx and allow ligand binding (Sabri et al 2000). This mechanism also encourages integrin clustering, as higher numbers of integrins increase the strength of the adhesion (Shimaoka et al 2003;Bunch 2010). Furthermore, the cluster size can also reflect the stiffness and thickness of the surrounding glycocalyx, as well as the membrane rigidity, with larger clusters being required in more rigid cellular microenvironments.…”

Conformational Complexity of Complement Component C3

“…In both cases, the binding site involves a metal-iondependent adhesion site (MIDAS) in the I domain 108 . Various structural studies 109,110 have shown that ligand binding to a MIDAS site involves an acidic residue of the ligand that completes the coordination sphere of the divalent ion bound at the MIDAS. In the integrins the ligand binding induces a large structural change of the C-terminal α-helix in the I domains, which activates the integrin [109][110][111] .…”

“…Various structural studies 109,110 have shown that ligand binding to a MIDAS site involves an acidic residue of the ligand that completes the coordination sphere of the divalent ion bound at the MIDAS. In the integrins the ligand binding induces a large structural change of the C-terminal α-helix in the I domains, which activates the integrin [109][110][111] . These I domains are structurally homologous to the VWA domain of factor B 33,34 .…”