title: Domain 1 of mucosal addressin cell adhesion molecule has an I1-set fold and a flexible integrin-binding loop.
abstract: Mucosal addressin cell adhesion molecule (MAdCAM) binds integrin α4β7. Their interaction directs lymphocyte homing to mucosa-associated lymphoid tissues. The interaction between the two immunoglobulin superfamily (IgSF) domains of MAdCAM and integrin α4β7 is unusual in its ability to mediate either rolling adhesion or firm adhesion of lymphocytes on vascular surfaces. We determined four crystal structures of the IgSF domains of MAdCAM to test for unusual structural features that might correlate with this functional diversity. Higher resolution 1.7- and 1.4-Å structures of the IgSF domains of MAdCAM in a previously described crystal lattice revealed two alternative conformations of the integrin-binding loop, which were deformed by large lattice contacts. New crystal forms in the presence of two different Fabs to MAdCAM demonstrate a shift in IgSF domain topology from the I2- to I1-set, with a switch of integrin-binding loop from CC' to CD. The I1-set fold and CD loop appear biologically relevant. The different conformations seen in crystal structures suggest that the integrin-binding loop of MAdCAM is inherently flexible. This contrasts with rigidity of the corresponding loops in vascular cell adhesion molecule, intercellular adhesion molecule (ICAM)-1, ICAM-2, ICAM-3, and ICAM-5 and may reflect a specialization of MAdCAM to mediate both rolling and firm adhesion by binding to different α4β7 integrin conformations.
authors.affiliation: Program in Cellular and Molecular Medicine, Children's Hospital Boston, and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Yamei
authors.initials: Y
authors.lastname: Yu
authors.forename: Jianghai
authors.initials: J
authors.lastname: Zhu
authors.forename: Po-Ssu
authors.initials: PS
authors.lastname: Huang
authors.forename: Jia-Huai
authors.initials: JH
authors.lastname: Wang
authors.forename: Nick
authors.initials: N
authors.lastname: Pullen
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Springer
mesh_terms: D000818:Animals; D016466:CHO Cells; D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D006801:Humans; D007136:Immunoglobulins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D039441:Integrin alpha4 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D039641:Integrin beta Chains / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009088:Mucoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D039641:Integrin beta Chains; C504265:MADCAM1 protein, human; D009088:Mucoproteins; C091368:integrin beta7; D039441:Integrin alpha4