Reports

A Zinc Clasp Structure Tethers Lck to T Cell Coreceptors CD4 and CD8

Peter W. Kim,^1,2 Zhen-Yu J. Sun,² Stephen C. Blacklow,³ Gerhard Wagner,² Michael J. Eck^1,2*

The T cell coreceptors CD4 and CD8 both associate via their cytoplasmic tails with the N-terminus of the Src-family tyrosine kinase Lck. These interactions require zinc and are critical for T cell development and activation. We examined the folding and solution structures of ternary CD4-Lck-Zn²⁺ and CD8-Lck-Zn²⁺ complexes. The coreceptor tails and the Lck N-terminus are unstructured in isolation but assemble in the presence of zinc to form compactly folded heterodimeric domains. The cofolded complexes have similar "zinc clasp" cores that are augmented by distinct structural elements. A dileucine motif required for clathrin-mediated endocytosis of CD4 is masked by Lck.

¹ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
² Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
³ Brigham and Women's Hospital and Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.

^* To whom correspondence should be addressed. E-mail: eck{at}red.dfci.harvard.edu

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CD4 and CD8: an inside-out coreceptor model for innate immune cells.

D. Gibbings and A. D. Befus (2009)
J. Leukoc. Biol. 86, 251-259
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The EVER Proteins as a Natural Barrier against Papillomaviruses: a New Insight into the Pathogenesis of Human Papillomavirus Infections.

M. Lazarczyk, P. Cassonnet, C. Pons, Y. Jacob, and M. Favre (2009)
Microbiol. Mol. Biol. Rev. 73, 348-370
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A Basic Patch on {alpha}-Adaptin Is Required for Binding of Human Immunodeficiency Virus Type 1 Nef and Cooperative Assembly of a CD4-Nef-AP-2 Complex.

R. Chaudhuri, R. Mattera, O. W. Lindwasser, M. S. Robinson, and J. S. Bonifacino (2009)
J. Virol. 83, 2518-2530
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Cytomegaloviral proteins that associate with the nuclear lamina: components of a postulated nuclear egress complex.

J. Milbradt, S. Auerochs, H. Sticht, and M. Marschall (2009)
J. Gen. Virol. 90, 579-590
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Regulated Movement of CD4 In and Out of the Immunological Synapse.

H. Kao, J. Lin, D. R. Littman, A. S. Shaw, and P. M. Allen (2008)
J. Immunol. 181, 8248-8257
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Conformational Rearrangement within the Soluble Domains of the CD4 Receptor Is Ligand-specific.

Ashish, I. J. Juncadella, R. Garg, C. D. Boone, J. Anguita, and J. K. Krueger (2008)
J. Biol. Chem. 283, 2761-2772
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Coreceptor Signal Strength Regulates Positive Selection but Does Not Determine CD4/CD8 Lineage Choice in a Physiologic In Vivo Model.

B. Erman, A. S. Alag, O. Dahle, F. van Laethem, S. D. Sarafova, T. I. Guinter, S. O. Sharrow, A. Grinberg, P. E. Love, and A. Singer (2006)
J. Immunol. 177, 6613-6625
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A CD8/Lck Transgene Is Able to Drive Thymocyte Differentiation.

R. C. Fragoso, S. Pyarajan, H. Y. Irie, and S. J. Burakoff (2006)
J. Immunol. 177, 6007-6017
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Apoptosis of Antigen-Specific T Lymphocytes upon the Engagement of CD8 by Soluble HLA Class I Molecules Is Fas Ligand/Fas Mediated: Evidence for the Involvement of p56lck, Calcium Calmodulin Kinase II, and Calcium-Independent Protein Kinase C Signaling Pathways and for NF-{kappa}B and NF-AT Nuclear Translocation.

P. Contini, M. Ghio, A. Merlo, A. Poggi, F. Indiveri, and F. Puppo (2005)
J. Immunol. 175, 7244-7254
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Carboxyl-Proximal Regions of Reovirus Nonstructural Protein {micro}NS Necessary and Sufficient for Forming Factory-Like Inclusions.

T. J. Broering, M. M. Arnold, C. L. Miller, J. A. Hurt, P. L. Joyce, and M. L. Nibert (2005)
J. Virol. 79, 6194-6206
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