A structure prediction for the ligand‐binding region of the integrin β subunit: evidence for the presence of a von Willebrand factor A domain

Abstract

The integrins are a family of cell surface receptors that mediate biologically important adhesive interactions. Integrin-Iigand binding has been extensively studied because of the potential for the development of anti-adhesive therapies, but the molecular basis of this interaction is still poorly understood. A conserved region near the N-terminus of the ~ subunit appears to be of particular importance in ligand binding, but to date this domain has not been expressed in isolation. As a prelude to expression and potential structure determination, we have performed a detailed structure prediction for this region. Primary, secondary and tertiary structure analyses indicate that the region folds into a von Willebrand factor A-domain, thereby potentially placing a previously characterised module at the centre of a key functional region.

Structure-Function of the Putative I-domain within the Integrin β2 Subunit

“…3) The positioning of these epitopes is consistent with an I-domain-like fold for this region of the ␤ 2 subunit, as proposed by several investigators (10,(15)(16)(17)(18)42 A number of studies have demonstrated the importance of the central region (residues 125-385 in ␤ 2 ) of the integrin ␤ subunits in ␣/␤ association. This region of ␤ 1 (residues 121-329) forms a heterodimer with ␣ 5 (160 -448) (47), and the same region of ␤ 3 (residues 111-318) complexes with ␣ IIb (1-233) (51 V 275 GSDNH between human and avian ␤ 3 was found to change the specificity of ␣ IIb /␤ 3 association (51).…”

“…It was proposed recently that the central region within the ␤ subunits (residues 125-385 for ␤ 2 ) folds into an I-domain-like structure, similar to that present in several integrin ␣ subunits (10,18). However, homology between the I-domains of the ␣ and ␤ subunits is very low, particularly in the C-terminal portions, and conflicting views exist in the literature as to whether this region assumes an I-domain fold or merely contains a metal binding MIDAS motif (DXSXS), such as that found in I-domains (14 -17).…”

“…This region is predicted to contain a MIDAS motif, and candidate residues for cation coordination have been identified by mutagenesis (14 -17). Protein sequence analysis suggests that this region may also fold into an I-domain-like structure (10,18). However, due to the low homology between the I-domains of the ␣ and ␤ subunits, it is uncertain whether this putative I-domain region does, indeed, fold into an I-domain, or merely contains a MI-DAS motif.…”

The Role of α and β Chains in Ligand Recognition by β7 Integrins

“…However, most integrins do not possess an A-domain in the ␣ chain, yet they are also dependent upon acidic residues in their ligands and have a similar requirement for divalent cations. A potential explanation is the proposal that all integrin ␤ chains have a region that adopts an A-domain-like fold (19,35,36). Indeed, all ␤ chains possess a relatively conserved region of ϳ250 amino acids that contains a DXSXS sequence, which, together with conserved downstream oxygenated residues, could form a complete MIDAS site.…”

Lymphocyte function-associated antigen-1 binding residues in intercellular adhesion molecule-2 (ICAM-2) and the integrin binding surface in the ICAM subfamily

“…By contrast, VCAM-1 and MAdCAM-1 bind to the ␣ 4 ␤ 1 and ␣ 4 ␤ 7 integrins, which lack an I domain (1). Therefore, the binding site in the integrin must differ, and may involve both a ␤-propeller domain predicted in all integrin ␣ subunits (8) and a domain with certain features resembling an I domain, including a Mg 2ϩ -binding site, predicted in the integrin ␤-subunit (4,9,10).…”