title: Rational design of intercellular adhesion molecule-1 (ICAM-1) variants for antagonizing integrin lymphocyte function-associated antigen-1-dependent adhesion.
abstract: The interaction between integrin lymphocyte function-associated antigen-1 (LFA-1) and its ligand intercellular adhesion molecule-1 (ICAM-1) is critical in immunological and inflammatory reactions but, like other adhesive interactions, is of low affinity. Here, multiple rational design methods were used to engineer ICAM-1 mutants with enhanced affinity for LFA-1. Five amino acid substitutions 1) enhance the hydrophobicity and packing of residues surrounding Glu-34 of ICAM-1, which coordinates to a Mg2+ in the LFA-1 I domain, and 2) alter associations at the edges of the binding interface. The affinity of the most improved ICAM-1 mutant for intermediate- and high-affinity LFA-1 I domains was increased by 19-fold and 22-fold, respectively, relative to wild type. Moreover, potency was similarly enhanced for inhibition of LFA-1-dependent ligand binding and cell adhesion. Thus, rational design can be used to engineer novel adhesion molecules with high monomeric affinity; furthermore, the ICAM-1 mutant holds promise for targeting LFA-1-ICAM-1 interaction for biological studies and therapeutic purposes.
authors.affiliation: CBR Institute for Biomedical Research, and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Song
authors.forename: Greg A
authors.initials: GA
authors.lastname: Lazar
authors.forename: Tanja
authors.initials: T
authors.lastname: Kortemme
authors.forename: Motomu
authors.initials: M
authors.lastname: Shimaoka
authors.forename: John R
authors.initials: JR
authors.lastname: Desjarlais
authors.forename: David
authors.initials: D
authors.lastname: Baker
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Springer
mesh_terms: D002448:Cell Adhesion; D002460:Cell Line; D019295:Computational Biology / Q000379:methods; D018076:DNA, Complementary / Q000378:metabolism; D005434:Flow Cytometry; D005818:Genetic Engineering; D014644:Genetic Variation; D005822:Genetic Vectors; D006801:Humans; D007249:Inflammation; D016023:Integrins; D018799:Intercellular Adhesion Molecule-1 / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D008274:Magnesium / Q000737:chemistry; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D015202:Protein Engineering; D017434:Protein Structure, Tertiary; D012984:Software
chemical_list: D018076:DNA, Complementary; D016023:Integrins; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1; D008274:Magnesium