Structures of the Alpha L I Domain and Its Complex with ICAM-1 Reveal a Shape-shifting Pathway for Integrin Regulation

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2003 Jan 16

PMID 12526797

Citations 237

Authors

Motomu Shimaoka

Tsan Xiao

Jin-Huan Liu

Yuting Yang

Yicheng Dong

Chang-Duk Jun

Alison McCormack

Rongguang Zhang

Andrzej Joachimiak

Junichi Takagi

Jia-Huai Wang

Timothy A Springer

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Determining Ligand Binding and Specificity Within the β-Integrin Family with a Novel Assay Platform.

Sommer-Pluss C, Leiggener C, Nikci E, Mancuso R, Rabbani S, Lamers C Biomolecules. 2025; 15(2).

PMID: 40001541 PMC: 11853025. DOI: 10.3390/biom15020238.

Molecular dynamics at immune synapse lipid rafts influence the cytolytic behavior of CAR T cells.

Gad A, Morris J, Godret-Miertschin L, Montalvo M, Kerr S, Berger H Sci Adv. 2025; 11(2):eadq8114.

PMID: 39792660 PMC: 11721525. DOI: 10.1126/sciadv.adq8114.

Ca transients on the T cell surface trigger rapid integrin activation in a timescale of seconds.

Li Y, Wang S, Zhang Y, Liu Z, Zheng Y, Zhang K Nat Commun. 2024; 15(1):6131.

PMID: 39033133 PMC: 11271479. DOI: 10.1038/s41467-024-50464-0.

The Role of Biophysical Factors in Organ Development: Insights from Current Organoid Models.

Wyle Y, Lu N, Hepfer J, Sayal R, Martinez T, Wang A Bioengineering (Basel). 2024; 11(6).

PMID: 38927855 PMC: 11200479. DOI: 10.3390/bioengineering11060619.

αI-domain of integrin Mac-1 binds the cytokine pleiotrophin using multiple mechanisms.

Nguyen H, Podolnikova N, Ugarova T, Wang X Structure. 2024; 32(8):1184-1196.e4.

PMID: 38729161 PMC: 11316656. DOI: 10.1016/j.str.2024.04.013.

References

Oxvig C, Lu C, Springer T . Conformational changes in tertiary structure near the ligand binding site of an integrin I domain. Proc Natl Acad Sci U S A. 1999; 96(5):2215-20. PMC: 26763. DOI: 10.1073/pnas.96.5.2215. View

Grakoui A, Bromley S, Sumen C, Davis M, Shaw A, Allen P . The immunological synapse: a molecular machine controlling T cell activation. Science. 1999; 285(5425):221-7. DOI: 10.1126/science.285.5425.221. View

Giancotti F, Ruoslahti E . Integrin signaling. Science. 1999; 285(5430):1028-32. DOI: 10.1126/science.285.5430.1028. View

van Kooyk Y, van Vliet S, Figdor C . The actin cytoskeleton regulates LFA-1 ligand binding through avidity rather than affinity changes. J Biol Chem. 1999; 274(38):26869-77. DOI: 10.1074/jbc.274.38.26869. View

Kallen J, Welzenbach K, Ramage P, Geyl D, Kriwacki R, Legge G . Structural basis for LFA-1 inhibition upon lovastatin binding to the CD11a I-domain. J Mol Biol. 1999; 292(1):1-9. DOI: 10.1006/jmbi.1999.3047. View

Legge G, Kriwacki R, Chung J, Hommel U, Ramage P, Case D . NMR solution structure of the inserted domain of human leukocyte function associated antigen-1. J Mol Biol. 2000; 295(5):1251-64. DOI: 10.1006/jmbi.1999.3409. View

Gottlieb A, Krueger J, Bright R, Ling M, Lebwohl M, Kang S . Effects of administration of a single dose of a humanized monoclonal antibody to CD11a on the immunobiology and clinical activity of psoriasis. J Am Acad Dermatol. 2000; 42(3):428-35. DOI: 10.1016/s0190-9622(00)90214-7. View

Emsley J, Knight C, Farndale R, Barnes M, Liddington R . Structural basis of collagen recognition by integrin alpha2beta1. Cell. 2000; 101(1):47-56. DOI: 10.1016/S0092-8674(00)80622-4. View

Huth J, Olejniczak E, Mendoza R, Liang H, Harris E, Lupher Jr M . NMR and mutagenesis evidence for an I domain allosteric site that regulates lymphocyte function-associated antigen 1 ligand binding. Proc Natl Acad Sci U S A. 2000; 97(10):5231-6. PMC: 25811. DOI: 10.1073/pnas.97.10.5231. View

10.

Constantin G, Majeed M, Giagulli C, Piccio L, Kim J, Butcher E . Chemokines trigger immediate beta2 integrin affinity and mobility changes: differential regulation and roles in lymphocyte arrest under flow. Immunity. 2001; 13(6):759-69. DOI: 10.1016/s1074-7613(00)00074-1. View

11.

Lu C, Shimaoka M, Zang Q, Takagi J, Springer T . Locking in alternate conformations of the integrin alphaLbeta2 I domain with disulfide bonds reveals functional relationships among integrin domains. Proc Natl Acad Sci U S A. 2001; 98(5):2393-8. PMC: 30149. DOI: 10.1073/pnas.041618598. View

12.

Shimaoka M, Lu C, Palframan R, von Andrian U, McCormack A, Takagi J . Reversibly locking a protein fold in an active conformation with a disulfide bond: integrin alphaL I domains with high affinity and antagonist activity in vivo. Proc Natl Acad Sci U S A. 2001; 98(11):6009-14. PMC: 33413. DOI: 10.1073/pnas.101130498. View

13.

Lupher Jr M, Harris E, Beals C, Sui L, Liddington R, Staunton D . Cellular activation of leukocyte function-associated antigen-1 and its affinity are regulated at the I domain allosteric site. J Immunol. 2001; 167(3):1431-9. DOI: 10.4049/jimmunol.167.3.1431. View

14.

Perrakis A, Harkiolaki M, Wilson K, Lamzin V . ARP/wARP and molecular replacement. Acta Crystallogr D Biol Crystallogr. 2001; 57(Pt 10):1445-50. DOI: 10.1107/s0907444901014007. View

15.

Chigaev A, Blenc A, Braaten J, Kumaraswamy N, Kepley C, Andrews R . Real time analysis of the affinity regulation of alpha 4-integrin. The physiologically activated receptor is intermediate in affinity between resting and Mn(2+) or antibody activation. J Biol Chem. 2001; 276(52):48670-8. DOI: 10.1074/jbc.M103194200. View

16.

Ma Q, Shimaoka M, Lu C, Jing H, Carman C, Springer T . Activation-induced conformational changes in the I domain region of lymphocyte function-associated antigen 1. J Biol Chem. 2002; 277(12):10638-41. DOI: 10.1074/jbc.M112417200. View

17.

Li R, Haruta I, Rieu P, Sugimori T, Xiong J, Arnaout M . Characterization of a conformationally sensitive murine monoclonal antibody directed to the metal ion-dependent adhesion site face of integrin CD11b. J Immunol. 2002; 168(3):1219-25. DOI: 10.4049/jimmunol.168.3.1219. View

18.

Schwartz M, Ginsberg M . Networks and crosstalk: integrin signalling spreads. Nat Cell Biol. 2002; 4(4):E65-8. DOI: 10.1038/ncb0402-e65. View

19.

Shimaoka M, Takagi J, Springer T . Conformational regulation of integrin structure and function. Annu Rev Biophys Biomol Struct. 2002; 31:485-516. DOI: 10.1146/annurev.biophys.31.101101.140922. View

20.

Alonso J, Essafi M, Xiong J, Stehle T, Arnaout M . Does the integrin alphaA domain act as a ligand for its betaA domain?. Curr Biol. 2002; 12(10):R340-2. DOI: 10.1016/s0960-9822(02)00852-7. View