Structural plasticity in Ig superfamily domain 4 of ICAM-1 mediates cell surface dimerization.
The Ig superfamily (IgSF) intercellular adhesion molecule-1 (ICAM-1) equilibrates between monomeric and dimeric forms on the cell surface, and dimerization enhances cell adhesion. A crystal structure of ICAM-1 IgSF domains (D) 3-5 revealed a unique dimerization interface in which D4s of two protomers fuse through edge beta-strands to form a single super beta-sandwich domain. Here, we describe a crystal structure at 2.7-A resolution of monomeric ICAM-1 D3-D5, stabilized by the monomer-specific Fab CA7. CA7 binds to D5 in a region that is buried in the dimeric interface and is distal from the dimerization site in D4. In monomeric ICAM-1 D3-D5, a 16-residue loop in D4 that is disordered in the dimeric structure could clearly be traced as a BC loop, a short C strand, and a CE meander with a cis-Pro followed by a solvent-exposed, flexible four-residue region. Deletions of 6 or 10 residues showed that the C-strand is essential for monomer stability, whereas a distinct six-residue deletion showed little contribution of the CE meander. Mutation of two inward-pointing Leu residues in edge beta-strand E to Lys increased monomer stability, confirming the hypothesis that inward-pointing charged side chains on edge beta-strands are an important design feature to prevent beta-supersheet formation. Overall, the studies reveal that monomer-dimer transition is associated with a surprisingly large, physiologically relevant, IgSF domain rearrangement.
Chen
Xuehui
X
Immune Disease Institute, Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Kim
Thomas Doohun
TD
Carman
Christopher V
CV
Mi
Li-Zhi
LZ
Song
Gang
G
Springer
Timothy A
TA
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry; D050440:Immunoglobulin Subunits / Q000737:chemistry*; D018799:Intercellular Adhesion Molecule-1 / Q000737:chemistry*; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid
D007140:Immunoglobulin Fab Fragments; D050440:Immunoglobulin Subunits; D018799:Intercellular Adhesion Molecule-1