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Originally published In Press as doi:10.1074/jbc.M002883200 on April 25, 2000

J. Biol. Chem., Vol. 275, Issue 29, 22202-22212, July 21, 2000
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The Top of the Inserted-like Domain of the Integrin Lymphocyte Function-associated Antigen-1 beta  Subunit Contacts the alpha  Subunit beta -Propeller Domain near beta -Sheet 3*

Qun ZangDagger , Chafen Lu§, Chichi Huang, Junichi Takagi, and Timothy A. Springer||

From the Center For Blood Research and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115

We find that monoclonal antibody YTA-1 recognizes an epitope formed by a combination of the integrin alpha L and beta 2 subunits of LFA-1. Using human/mouse chimeras of the alpha L and beta 2 subunits, we determined that YTA-1 binds to the predicted inserted (I)-like domain of the beta 2 subunit and the predicted beta -propeller domain of the alpha L subunit. Substitution into mouse LFA-1 of human residues Ser302 and Arg303 of the beta 2 subunit and Pro78, Thr79, Asp80, Ile365, and Asn367 of the alpha L subunit is sufficient to completely reconstitute YTA-1 reactivity. Antibodies that bind to epitopes that are nearby in models of the I-like and beta -propeller domains compete with YTA-1 monoclonal antibody for binding. The predicted beta -propeller domain of integrin alpha  subunits contains seven beta -sheets arranged like blades of a propeller around a pseudosymmetry axis. The antigenic residues cluster on the bottom of this domain in the 1-2 loop of blade 2, and on the side of the domain in beta -strand 4 of blade 3. The I domain is inserted between these blades on the top of the beta -propeller domain. The antigenic residues in the beta  subunit localize to the top of the I-like domain near the putative Mg2+ ion binding site. Thus, the I-like domain contacts the bottom or side of the beta -propeller domain near beta -sheets 2 and 3. YTA-1 preferentially reacts with activated LFA-1 and is a function-blocking antibody, suggesting that conformational movements occur near the interface it defines between the LFA-1 alpha  and beta  subunits.

* This work was supported by Grant CA31798 from the National Institutes of Health.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Present address: Biogen, Inc., Cambridge, MA 02142.

§ Present address: Millennium Pharmaceuticals, Cambridge, MA 02142.

Present address: Pfizer Central Research, Groton, CT 06340.

|| To whom correspondence should be addressed: Center For Blood Research and Dept. of Pathology, Harvard Medical School, 200 Longwood Ave., Boston, MA 02115. Tel.: 617-278-3200; Fax: 617-278-3232.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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