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Blood, 15 April 2007, Vol. 109, No. 8, pp. 3513-3520. Prepublished online as a Blood First Edition Paper on December 14, 2006; DOI 10.1182/blood-2005-11-056689. This Article Full Text (PDF) All Versions of this Article: blood-2005-11-056689v1 109/8/3513    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gupta, V. Articles by Arnaout, M. A. Search for Related Content PubMed PubMed Citation Articles by Gupta, V. Articles by Arnaout, M. A. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 30, 2005 Accepted December 7, 2006 The -tail domain (TD) regulates physiologic ligand binding to integrin CD11b/CD18 Vineet Gupta, Annette Gylling, Jose-Louis Alonso, Takashi Sugimori, Petre Ianakiev, Jiang-Ping Xiong, and M. Amin Arnaout* Nephrology Division, Leukocyte Biology & Inflammation Prog., Structural Biology Prog., Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States * Corresponding author; email: arnaout{at}receptor.mgh.harvard.edu. Crystallographic and electron microscopy studies revealed genuflexed (bent) integrins in both unliganded (inactive) and physiologic ligand-bound (active) states, suggesting that local conformational changes are sufficient for activation. Herein we have explored the role of local changes in the contact region between the membrane-proximal -tail domain (TD) and the ligand-binding A domain of the bent conformation, in regulating interaction of integrin CD11b/CD18 (M2) with its physiologic ligand iC3b. We replaced the TD CD loop residues D658GMD of the CD18 (2) subunit with the equivalent D672SSG of the 3 subunit, with AGAA or with NGTD, expressed the respective heterodimeric receptors either transiently in epithelial HEK293T cells or stably in leukocytes (K562), and measured their ability to bind iC3b and to conformation-sensitive mAbs. In the presence of the physiologic divalent cations Ca2+ plus Mg2+ (at 1mM each), the modified integrins showed increased (in HEK293) or constitutive (in K562) binding to iC3b, compared to wild-type receptors. K562 expressing the TD modified integrins bound in Ca2+ /Mg2+ to the A-directed high-affinity reporter mAb 24 but not to mAb KIM127, a reporter of genu-straightened state. These data identify a role for the membrane proximal TD as an allosteric modulator of integrin activation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Blood orchestrates a leukocyte integrin trio Joel S. Bennett Blood 2007 109: 3137-3138. [Full Text] [PDF] This article has been cited by other articles: J.-P. Xiong, B. Mahalingham, J. L. Alonso, L. A. Borrelli, X. Rui, S. Anand, B. T. Hyman, T. Rysiok, D. Muller-Pompalla, S. L. Goodman, et al. Crystal structure of the complete integrin {alpha}V{beta}3 ectodomain plus an {alpha}/{beta} transmembrane fragment J. Cell Biol., August 24, 2009; 186(4): 589 - 600. [Abstract] [Full Text] [PDF]

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