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J. Biol. Chem., Vol. 282, Issue 30, 22023-22032, July 27, 2007

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Structural and Functional Characterization of a Novel T Cell Receptor Co-regulatory Protein Complex, CD97-CD55^*

Rachel J. M. Abbott¹, Ian Spendlove¹², Pietro Roversi, Hannah Fitzgibbon, Vroni Knott^¶, Peter Teriete^¶, James M. McDonnell^¶, Penny A. Handford^¶, and Susan M. Lea³

From the Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, United Kingdom, the Academic Clinical Oncology, School of Molecular Medical Sciences, City Hospital, University of Nottingham, Hucknall Road, Nottingham NG5 1PB, United Kingdom, and the ^¶Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom

CD97, the archetypal member of the EGF-TM7 protein family, is constitutively expressed on granulocytes and monocytes and rapidly up-regulated on T and B cells following activation. The key isoform of CD97 expressed on leukocytes binds the complement regulatory protein CD55 (also termed decay-accelerating factor). CD97 has been shown recently to mediate co-stimulation of T cells via CD55. Here, we demonstrate that blocking the interaction between CD55 on monocytes and CD97 on T cells leads to inhibition of proliferation and interferon- secretion. This implies that bidirectional interactions between CD97 and CD55 are involved in T cell regulation. Structural studies presented here reveal the molecular basis for this activity. We have solved the structure of EMR2, a very close homolog of CD97, using x-ray crystallography. NMR-based chemical shift mapping of the EMR2-CD55 interaction has allowed us to generate a model for the CD97-CD55 complex. The structure of the complex reveals that the T cell and complement regulatory activities of CD55 occur on opposite faces of the molecule. This suggests that CD55 might simultaneously regulate both the innate and adaptive immune responses, and we have shown that CD55 can still regulate complement when bound to CD97.

Received for publication, March 26, 2007

The atomic coordinates and structure factors (code 2BOU, 2BO2, and 2BOX) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by a Medical Research Council studentship (to R. J. M. A.) and Medical Research Council Grants G0400775 (to S. M. L. for P. R.) and G0000164 (to P. A. H. and V. K.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1 and Table I.

¹ Both authors contributed equally to this work.

¹ To whom correspondence may be addressed. Tel.: 44-1158-231-857; Fax: 44-1158-230-759; E-mail: ian.spendlove{at}nottingham.ac.uk.

¹ To whom correspondence may be addressed. Tel.: 44-1865-275-181; Fax: 44-1865-275-182; E-mail: susan.lea{at}path.ox.ac.uk.

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