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2 Subunit Reveals Regions that Become Exposed Upon Receptor Activation1
Center for Blood Research, Department of Pathology, Harvard Medical School, Boston, MA 02115
The cysteine-rich repeats in the stalk region of integrin 
subunits appear to convey signals impinging on the cytoplasmic domains
to the ligand-binding headpiece of integrins. We have examined the
functional properties of mAbs to the stalk region and mapped their
epitopes, providing a structure-function map. Among a panel of 14 mAbs
to the 2 subunit, one, KIM127, preferentially bound to
L2 that was activated by mutations in the
cytoplasmic domains, and by Mn2+. KIM127 also bound
preferentially to the free 2 subunit compared with
resting L2. Activating 2
mutations also greatly enhanced binding of KIM127 to integrins
M2 and X2.
Thus, the KIM127 epitope is shielded by the subunit, and becomes
reexposed upon receptor activation. Three other mAbs, CBR LFA-1/2,
MEM48, and KIM185, activated L2 and bound
equally well to resting and activated L2,
differentially recognized resting M2 and
X2, and bound fully to activated
M2 and X2.
The KIM127 epitope localizes within cysteine-rich repeat 2, to residues
504, 506, and 508. By contrast, the two activating mAbs CBR LFA-1/2 and
MEM48 bind to overlapping epitopes involving residues 534, 536, 541,
543, and 546 in cysteine-rich repeat 3, and the activating mAb KIM185
maps near the end of cysteine-rich repeat 4. The nonactivating mAbs,
6.7 and CBR LFA-1/7, map more N-terminal, to subregions 344–432 and
432–487, respectively. We thus define five different 2
stalk subregions, mAb binding to which correlates with effect on
activation, and define regions in an interface that becomes exposed
upon integrin activation.
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M. Bjorklund, P. Heikkila, and E. Koivunen Peptide Inhibition of Catalytic and Noncatalytic Activities of Matrix Metalloproteinase-9 Blocks Tumor Cell Migration and Invasion J. Biol. Chem., July 9, 2004; 279(28): 29589 - 29597. [Abstract] [Full Text] [PDF]
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B.-H. Luo, K. Strokovich, T. Walz, T. A. Springer, and J. Takagi Allosteric {beta}1 Integrin Antibodies That Stabilize the Low Affinity State by Preventing the Swing-out of the Hybrid Domain J. Biol. Chem., June 25, 2004; 279(26): 27466 - 27471. [Abstract] [Full Text] [PDF]
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W. Yang, M. Shimaoka, A. Salas, J. Takagi, and T. A. Springer Intersubunit signal transmission in integrins by a receptor-like interaction with a pull spring PNAS, March 2, 2004; 101(9): 2906 - 2911. [Abstract] [Full Text] [PDF]
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W. Yang, M. Shimaoka, J. Chen, and T. A. Springer Activation of integrin {beta}-subunit I-like domains by one-turn C-terminal {alpha}-helix deletions PNAS, February 24, 2004; 101(8): 2333 - 2338. [Abstract] [Full Text] [PDF]
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S. Fukuda and G. W. Schmid-Schonbein Regulation of CD18 expression on neutrophils in response to fluid shear stress PNAS, November 11, 2003; 100(23): 13152 - 13157. [Abstract] [Full Text] [PDF]
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Y.-M. Xiong, J. Chen, and L. Zhang Modulation of CD11b/CD18 Adhesive Activity by Its Extracellular, Membrane-Proximal Regions J. Immunol., July 15, 2003; 171(2): 1042 - 1050. [Abstract] [Full Text] [PDF]
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M. R. Marwali, J. Rey-Ladino, L. Dreolini, D. Shaw, and F. Takei Membrane cholesterol regulates LFA-1 function and lipid raft heterogeneity Blood, July 1, 2003; 102(1): 215 - 222. [Abstract] [Full Text] [PDF]
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J. Takagi, N. Beglova, P. Yalamanchili, S. C. Blacklow, and T. A. Springer Definition of EGF-like, closely interacting modules that bear activation epitopes in integrin beta subunits PNAS, September 25, 2001; 98(20): 11175 - 11180. [Abstract] [Full Text] [PDF]
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S.-M. Tan, M. K. Robinson, K. Drbal, Y. van Kooyk, J. M. Shaw, and S. K. A. Law The N-terminal Region and the Mid-region Complex of the Integrin beta 2 Subunit J. Biol. Chem., September 21, 2001; 276(39): 36370 - 36376. [Abstract] [Full Text] [PDF]
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S. Fagerholm, N. Morrice, C. G. Gahmberg, and P. Cohen Phosphorylation of the Cytoplasmic Domain of the Integrin CD18 Chain by Protein Kinase C Isoforms in Leukocytes J. Biol. Chem., January 11, 2002; 277(3): 1728 - 1738. [Abstract] [Full Text] [PDF]
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