Peter D. Sun, Ph.D.

Chief, Structural Immunology Section

Dr. Sun obtained his Ph.D. from the Molecular Biology Institute, University of Oregon, for the study of structure and thermostability of phage T4 lysozyme using X-ray crystallography. He then joined the National Institute of Digestive and NIDDK for his postdoctoral training in 1991, focusing on the structure and function of cytokines. In particular, he determined the crystal structure of a human transforming growth factor, TGF-beta 2. He joined NIAID in 1994.

Description of Research Program

Natural killer (NK) cells are a lineage of bone marrow-derived, large granular lymphocytes that are capable of lysing some tumor- and virus-infected cells as well as mediating allorecognition. They are particularly important in the early stages of pathogen invasion—before cytotoxic T lymphocytes are activated, NK cells mediate innate immunity.

The most interesting aspect of NK-cell function is that their activation appears to be based on the "missing self" hypothesis, a very different mechanism from the activation of T cells. It is now known that there are two sets of receptors on a given NK cell surface: the activating receptors and the inhibitory receptors. Together they control target recognition and lysis.

One family of inhibitory receptors on NK cells, termed killer inhibitory receptors (KIR), has been identified recently on human NK cells to have immunoglobulin-like extracellular ligand binding domains. Members of this family have either two (p58 molecules) or three (p70 molecules) Ig-like domains. It has been shown by the work of Eric Long and others that the protective effect of KIR against cell lysis is directly through the binding and recognition of class I HLA molecules. Furthermore, these receptors display HLA allotype specificity, as defined by two allotype specific mAbs, GL183, and EB6, and several residues in the region of amino acid 77-80 of the HLA heavy chain have been implicated in contributing to this specificity.

We are interested in understanding at the molecular level the process of specific recognition of HLA molecules by p58 receptors using X-ray crystallography. We have constructed a bacterial expression system to express and purify a human soluble receptor, p58cl43. It binds to GL183-specific HLA-C allotypes. In collaboration with Dr. Andrew Brooks of the Laboratory of Immunogenetics, we are in the process of identifying the appropriate peptide ligands of a HLA-Cw4 that are able to interact with this receptor. It is our goal to study the crystallization and structure determination of the complex between this p58 receptor and its HLA ligand.

CD16, an immunoglobulin Fc receptor, functions as the primary activating receptor on NK cells and mediates positive signals. Activation of CD16 upon antibody cross-linking results in lysis of target cells. CD16 is also known to play a role in T-cell development and function. In humans, certain auto-reactive IgG immune complexes cause symptoms of an inflammatory response and autoimmune diseases, such as lupus and rheumatoid arthritis. Their extracellular ligand-binding domain consists of two immunoglobulin modules and their cytoplasmic domain interacts with ITAM-containing co-receptors. To date, there has not been a crystal structure available for the family of Fc receptors. As a result, the molecular mechanism governing the activation of Fc receptors remains largely unknown. We hope to reveal the active conformation of the receptor through the structure determination and to define important residues on both the receptor and the MHC molecules involved in this receptor-ligand recognition.

Awards

NIH Director's Award 2001

Research Group Members

Danielle Atibalentja, Jennifer Ford, Christine Foster, Biniam Hagos, Agniswamy Johnson, Zhiqiang Lu, Andy Patamawenu, Sergei Radaev, Greg Snyder, Zhongcheng Zou.

Selected Publications

(Search PubMed.)

Radaev S, Sun PD. Crystallization of protein-protein complexes. J Appl Chryst. 2002. 35: 674-676.

Radaev S, Sun PD. Structure and function of natural killer cell surface receptors. Annu Rev Biophys Biomol Struct. 2003. 32: 93-114.

Radaev S, Kattah M, Zou Z, Colonna M, Sun PD. Making sense of the diverse ligand recognition by NKG2D. J Immunol. 2002. 169(11): 6279-6285.

Boesen CC, Radaev S, Motyka SA, Patamawenu A, Sun PD. The 1.1 A crystal structure of human TGF-beta type II receptor ligand binding domain. Structure (Camb). 2002. 10(7): 913-919.

Sun PD, Radaev S, Kattah M. Generating isomorphous heavy-atom derivatives by a quick-soak method. Part I: test cases. Acta Cryst. 2002. D58:1092-1098.

Sun PD, Radaev S. Generating isomorphous heavy-atom derivatives by a quick-soak method. Part II: phasing of new structures. Acta Cryst. 2002. 58(Pt 7): 1099-1103.

Boesen CC, Motyka SA, Patamawenu A, Sun PD. Crystallization and preliminary crystallographic studies of human TGF-b type II receptor ligand binding domain. Acta Cryst. 2002. 58(Pt 7):1214-1216.

Radaev S and Sun P. Recognition of immunoglobulins by Fcg receptors. Mol Immunol. 2002. 38: 1073-1083.

Boyington JC and Sun PD. A structural perspective on MHC class I recognition by killer cell immunoglobulin-like receptors. Mol Immunol. 2002. 38: 1007-1021.

Sun P. To kill or not to kill. Mol Immunol. 2002. 38: 1005-1006.

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