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(LFA-1) 2Β L Α Integrin Subunit I Domain in Regulation of 2Β The

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(LFA-1) 2Β L Α Integrin Subunit I Domain in Regulation of 2Β The The Role of the CPNKEKEC Sequence in the β2 Subunit I Domain in Regulation of Integrin αLβ2 (LFA-1) This information is current as Tetsuji Kamata, Kenneth Khiem Tieu, Takehiko Tarui, of September 27, 2021. Wilma Puzon-McLaughlin, Nancy Hogg and Yoshikazu Takada J Immunol 2002; 168:2296-2301; ; doi: 10.4049/jimmunol.168.5.2296 http://www.jimmunol.org/content/168/5/2296 Downloaded from References This article cites 43 articles, 27 of which you can access for free at: http://www.jimmunol.org/content/168/5/2296.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 27, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2002 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. ␤ The Role of the CPNKEKEC Sequence in the 2 Subunit I ␣ ␤ 1 Domain in Regulation of Integrin L 2 (LFA-1) Tetsuji Kamata,2* Kenneth Khiem Tieu,* Takehiko Tarui,* Wilma Puzon-McLaughlin,* Nancy Hogg,† and Yoshikazu Takada2* ␣ ␣ ␤ The L I (inserted or interactive) domain of integrin L 2 undergoes conformational changes upon activation. Recent studies show ␣ ␤ that the isolated, activated L I domain is sufficient for strong ligand binding, suggesting the 2 subunit to be only indirectly ␣ ␤ involved. It has been unclear whether the activity of the L I domain is regulated by the 2 subunit. In this study, we demonstrate ␤ ␤ that swapping the disulfide-linked CPNKEKEC sequence (residues 169–176) in the 2 I domain with a corresponding 3 sequence, 2؉ ␤ ␣ 174 or mutating Lys to Thr, constitutively activates L 2 binding to ICAM-1. These mutants do not require Mn for ICAM-1 2؉ binding and are insensitive to the inhibitory effect of Ca . We have also localized a component of the mAb 24 epitope (a reporter Downloaded from ␤ 173 175 ␤ of 2 integrin activation) in the CPNKEKEC sequence. Glu and Glu of the 2 I domain are identified as critical for mAb ␤ 24 binding. Because the epitope is highly expressed upon 2 integrin activation, it is likely that the CPNKEKEC sequence is ␣ exposed or undergoes conformational changes upon activation. Deletion of the L I domain did not eliminate the mAb 24 epitope. ␣ This confirms that the L I domain is not critical for mAb 24 binding, and indicates that mAb 24 detects a change expressed in ␤ ␤ part in the 2 subunit I domain. These results suggest that the CPNKEKEC sequence of the 2 I domain is involved in regulating ␣ http://www.jimmunol.org/ the L I domain. The Journal of Immunology, 2002, 168: 2296–2301. ␣ ␤ ␣␤ ␣ he integrin L 2 (LFA-1, CD11a/CD18) is an het- domain of the integrin subunits undergoes conformational ␤ ␣ ␤ erodimeric receptor of the 2 integrin family. L 2 is ex- changes on activation. The two different conformations of the in- T pressed on all leukocytes, is crucial to the inflammatory tegrin ␣ subunit I domain (open and closed) have recently been process, and mediates adhesion to ligands ICAM-1, ICAM-2, and defined, and it has been proposed that these two structures repre- ␣ ␤ ICAM-3 (reviewed in Refs. 1–4). The adhesiveness of L 2 can sent the high-affinity and low-affinity conformations, respectively be dynamically regulated by intracellular signals (inside-out sig- (11–13). Recently, Kallen et al. (14) found that a chemical, lova- 2ϩ ␣ ␣ ␤ naling) (5). Activation from the outside of the cell with Mg and statin, binds to the L I domain and blocks L 2-ligand interac- ␣ ␤ by guest on September 27, 2021 EGTA results in the formation of a high-affinity form of L 2,as tion. It is likely that lovastatin blocks the conformational change shown by an increased ability to bind to soluble ICAM-1, and in that occurs when the closed (inactive) form alters to the open (ac- ␣ ␣ the expression of an activation reporter epitope recognized by tive) form. The M and L I domain, with an open and closed mAb 24 (2, 6, 7). mAb 24 was originally proposed to recognize an conformation, has been generated by site-directed mutagenesis ␤ ␣ ␣ ␣ ␣ ␣ epitope common to all 2 integrin subunits ( L, M, X) (6–9). (15, 16). The isolated L I domain with locked open conformation ␣ 3 ␤ The L subunit has an I (inserted or interactive) domain of is sufficient for ligand binding, suggesting that the 2 subunit may ϳ200 amino acid residues that is critically involved in ligand bind- be only indirectly involved in ligand binding (17). ing. The I domain consists of a central ␤ sheet, surrounded by It has been proposed that the integrin ␤ subunit also has an I seven ␣ helices, which is folded as a globular domain (Rossmann- domain structure within the N-terminal region, which has been ␣ ␤ fold). At the top of the globular domain, the I domain has a metal validated in the recent v 3 crystal structure (11, 18). It is unclear ion-dependent adhesive site (MIDAS) that is involved in coordi- ␤ how and whether the 2 subunit I domain is involved in the con- nating cations Mg2ϩ or Mn2ϩ and in binding ligands (10). The I ␣ ␤ formational changes that L 2 undergoes upon activation. We have reported that the disulfide-linked predicted loop of the inte- ␤ grin 3 I domain (the CYDMKTTC sequence) is critically in- *Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037; volved in the ligand binding and specificity of the non-I domain † and Leukocyte Adhesion Laboratory, Imperial Cancer Research Fund, London, integrin ␣ ␤ (19). Also, it has been proposed that the loop is United Kingdom v 3 localized within the putative ligand-binding pocket in the non-I Received for publication June 20, 2001. Accepted for publication December 13, 2001. domain integrin ␣ ␤ (20). The recent ␣ ␤ crystal structure The costs of publication of this article were defrayed in part by the payment of page IIb 3 v 3 charges. This article must therefore be hereby marked advertisement in accordance shows that the CYDMKTTC sequence is actually exposed to the ␤ with 18 U.S.C. Section 1734 solely to indicate this fact. surface in the headpiece of the 3 subunit (18) (Fig. 1). In the 1 This work was supported by National Institutes of Health Grant GM49899 (to Y.T.) present study, we designed mutagenesis experiments to determine and by Department of the Army Grant DAMD17-97-1-7105 (to T.K.). This is pub- the potential function of the disulfide-linked CPNKEKEC se- lication 14111-VB from The Scripps Research Institute. ␤ quence in the 2 subunit I domain. We show that mutation of the 2 Address correspondence and reprint requests to Dr. Yoshikazu Takada, Department ␣ ␤ of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La CPNKEKEC sequence constitutively activates L 2. We propose ␤ Jolla, CA 92037. E-mail address: [email protected], or Dr. Tetsuji Kamata at the that this sequence in the 2 I domain is critically involved in reg- current address: Department of Anatomy, Keio University School of Medicine, 35 ␣ ulating the L subunit I domain. We found that the CPNKEKEC Shinanomachi, Shinjuku-ku, Tokyo 160, Japan. E-mail address: [email protected]. ␤ keio.ac.jp sequence of 2 is part of the mAb 24 epitope, indicating that mAb ␤ 3 Abbreviations used in this paper: I, inserted or interactive; CHO, Chinese hamster 24 detects a change in the 2 I domain and/or in interdomain ovary; MIDAS, metal ion-dependent adhesive site. interaction on activation. Copyright © 2002 by The American Association of Immunologists 0022-1767/02/$02.00 The Journal of Immunology 2297 Materials and Methods Materials ␤ mAb 24 was generated as previously described (6). mAbs IB-4 (anti- 2) ␣ (21) and TS 1/22 (anti- L) (22) were obtained from American Type Cul- ␤ ture Collection (ATCC, Manassas, VA). mAbs MEM-48 (anti- 2) and ␣ MEM-83 (anti- L) (23) were provided by V. Horejsi (Institute of Molec- ular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic). ICAM-1/mouse C␬ fusion protein was obtained from G. Weitz ␤ (Novartis, Basel, Switzerland). Rat anti-mouse 2 mAb (C71/16) was pur- ␤ chased from BD PharMingen (San Diego, CA). Mouse 2 cDNA was obtained from ATCC. ␣ ␤ cDNA construct and expression of L 2 ␣ ␤ ␤ Human L, human 2, and mouse 2 cDNAs were subcloned into pBJ-1 (24), and site-directed mutagenesis was conducted using unique restriction site elimination (25). The presence of mutations was confirmed by DNA ␣ ␤ sequencing. L and 2 cDNAs in the pBJ-1 vector were transfected into Chinese hamster ovary (CHO) cells by electroporation. Flow cytometry was conducted as described (26). In some experiments, 0.5 mM Mn2ϩ was added to induce mAb 24 binding. Downloaded from Adhesion assays ␣ ␤ Adhesion of CHO and K562 cells expressing L 2 to ICAM-1 was assayed as described (27). Briefly, wells of 96-well Immulon-2 plates were coated with goat anti-mouse C␬ chain polyclonal Ab (Caltag Laboratories, South San Francisco, CA; 0.4 ␮g/well in 100 ␮l of PBS), and then with ICAM- 1/mouse C␬ fusion protein (8 ␮g/ml), unless otherwise specified.
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