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J. Biol. Chem., Vol. 279, Issue 32, 33816-33828, August 6, 2004

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The LFA-1-associated Molecule PTA-1 (CD226) on T Cells Forms a Dynamic Molecular Complex with Protein 4.1G and Human Discs Large^*

Kylie J. Ralston, Samantha L. Hird, Xinhai Zhang, Judith L. Scott, Boquan Jin, Rick F. Thorne¶, Michael C. Berndt||, Andrew W. Boyd**, and Gordon F. Burns

From the Cancer Research Unit, School of Biomedical Sciences, The University of Newcastle, University Drive, Callaghan, New South Wales 2308, Australia, the Department of Immunology, The 4th Military Medical University, Xi'an 710032, People's Republic of China, the ^||Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3168, Australia, and the ^**Division of Cancer and Cell Biology, Queensland Institute of Medical Research, Royal Brisbane Hospital PO, Brisbane, Queensland 4029, Australia

Clustering of the T cell integrin, LFA-1, at specialized regions of intercellular contact initiates integrin-mediated adhesion and downstream signaling, events that are necessary for a successful immunological response. But how clustering is achieved and sustained is not known. Here we establish that an LFA-1-associated molecule, PTA-1, is localized to membrane rafts and binds the carboxyl-terminal domain of isoforms of the actin-binding protein 4.1G. Protein 4.1 is known to associate with the membrane-associated guanylate kinase homologue, human discs large. We show that the carboxyl-terminal peptide of PTA-1 also can bind human discs large and that the presence or absence of this peptide greatly influences binding between PTA-1 and different isoforms of 4.1G. T cell stimulation with phorbol ester or PTA-1 cross-linking induces PTA-1 and 4.1G to associate tightly with the cytoskeleton, and the PTA-1 from such activated cells now can bind to the amino-terminal region of 4.1G. We propose that these dynamic associations provide the structural basis for a regulated molecular adhesive complex that serves to cluster and transport LFA-1 and associated molecules.

Received for publication, January 30, 2004 , and in revised form, April 14, 2004.

^* This work was supported by a grant from the National Health and Medical Research Council of Australia and by National Natural Science Foundation of China Grant 30030130. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Supported by a Brawn Fellowship from the University of Newcastle. Present address: Breakthrough Breast Cancer Centre, Institute of Cancer Research, 237 Fulham Rd., Chelsea, London SW3-6JB, United Kingdom.

To whom correspondence should be addressed. Tel.: 61-2-49217860; Fax: 61-2-49217867; E-mail: Gordon.Burns{at}newcastle.edu.au.

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