Structures of the alpha L I domain and its complex with ICAM-1 reveal a shape-shifting pathway for integrin regulation.
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.
Shimaoka
Motomu
M
The Center for Blood Research, Department of Pathology, Department of Anesthesia, Department of Pediatrics, Boston, Massachusetts 02115.
Xiao
Tsan
T
The Center for Blood Research, Department of Pathology, Department of Anesthesia, Department of Pediatrics, Boston, Massachusetts 02115.
Liu
Jin-Huan
JH
Dana-Farber Cancer Institute, Department of Pediatrics, Department of Medicine, Department of Biological Chemistry, Department of Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115.
Yang
Yuting
Y
Dana-Farber Cancer Institute, Department of Pediatrics, Department of Medicine, Department of Biological Chemistry, Department of Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115.
Dong
Yicheng
Y
Dana-Farber Cancer Institute, Department of Pediatrics, Department of Medicine, Department of Biological Chemistry, Department of Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115.
Jun
Chang-Duk
CD
The Center for Blood Research, Department of Pathology, Department of Anesthesia, Department of Pediatrics, Boston, Massachusetts 02115.
McCormack
Alison
A
The Center for Blood Research, Department of Pathology, Department of Anesthesia, Department of Pediatrics, Boston, Massachusetts 02115.
Zhang
Rongguang
R
Biosciences Division, Argonne National Laboratory, Argonne, Illinois 60439.
Joachimiak
Andrzej
A
Biosciences Division, Argonne National Laboratory, Argonne, Illinois 60439.
Takagi
Junichi
J
The Center for Blood Research, Department of Pathology, Department of Anesthesia, Department of Pediatrics, Boston, Massachusetts 02115.
Wang
Jia-Huai
JH
Dana-Farber Cancer Institute, Department of Pediatrics, Department of Medicine, Department of Biological Chemistry, Department of Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115.
Springer
Timothy A
TA
The Center for Blood Research, Department of Pathology, Department of Anesthesia, Department of Pediatrics, Boston, Massachusetts 02115.
D019943:Amino Acid Substitution; D000818:Animals; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D004220:Disulfides / Q000737:chemistry; D004926:Escherichia coli / Q000235:genetics; D005973:Glutamine / Q000737:chemistry / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D008274:Magnesium / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013059:Spectrum Analysis, Raman; D020349:Surface Plasmon Resonance
D004220:Disulfides; D016023:Integrins; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1; D005973:Glutamine; D018799:Intercellular Adhesion Molecule-1; D008274:Magnesium