Tsan “Sam” Xiao, Ph.D.

Investigator
Chief, Structural Immunobiology Unit

Dr. Xiao received his Ph.D. in molecular biophysics from the University of Texas Southwestern Medical Center at Dallas, where he studied essential signal transducing molecules involved in Drosophila innate immunity and development. Following his postdoctoral research on integrins at the CBR Institute for Biomedical Research, Harvard Medical School, he joined the Laboratory of Immunology in the spring of 2006.

Description of Research Program

The Structural Immunobiology Unit studies innate immune signaling pathways. Our research program integrates functional studies with extensive structural analysis of pattern recognition receptors (PRRs) in complex with their ligands as well as downstream adapters and effector molecules. Both membrane-bound (such as the Toll-like receptors) and cytoplasmic (such as the CATERPILLAR family members and RIG-I/MDA5 antiviral proteins) PRRs are targeted. A critical feature of these innate immune receptors is that they distinguish among various classes of pathogen-specific molecules while retaining responsiveness to a large number of related molecules within a given biochemical class. Understanding such “broad” reactivity at the atomic level is one of the primary goals of the program.

Ligand binding by the PRRs not only initiates intracellular signaling cascades leading to innate immune responses against infections, but also allows the innate immune system to orchestrate and potentiate the activities of the adaptive immune system. Our research aims to decipher this signaling network by studying structures of macromolecular complexes using x-ray crystallography in conjunction with other biophysical and biochemical techniques.

The ultimate goal of these studies is to understand the molecular mechanisms underlying innate immune defenses and the cross-talk between the innate and adaptive immune systems. Knowledge gained from these studies will be used to guide the development of new therapeutics that target infectious diseases and cancer.

Figure 1. The innate immune response

Figure 2. Signal transduction pathways in innate immunity View enlarged version of Figure 2.

To facilitate structural studies, we are currently establishing protein expression, purification and crystallization systems for the PRRs and their downstream adaptors and effectors. Recombinant protein production systems using E. coli and insect and mammalian cells as expression hosts are employed and parallel processing is emphasized.

One of the main technical rate-limiting steps in structural studies is the difficulty in obtaining large quantities of purified functional proteins. We are addressing this issue utilizing the Topaz® protein crystallization system from Fluidigm, which uses a small amount of sample for each crystallization experiment. Minimal sample consumption allows efficient screening of both crystallization conditions and upstream protein production schemes involving various constructs, vectors, expression tags and hosts. We will also use a crystallization robot Mosquito from Molecular Dimensions, Inc. to improve our throughput.

Memberships

• American Crystallographic Association
• American Chemical Society
• Sigma Xi, the Scientific Research Society

Research Group Members

Jiansheng Jiang (301-594-2097), Ruiling Mu (301-594-2099), Patrick T. Smith (301-496-5070), Greg A. Snyder (301-402-7523), Tinghe Wu (301-594-2114), Peter E. Hemenegildo (301-594-2202)

Selected Publications

(View list in PubMed)

Xiao T, Takagi J, Coller BS, Wang J-H, Springer TA. Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics. Nature. 2004. 432, 59-67.

Xie C, Shimaoka M, Xiao T, Schwab P, Klickstein LB, Springer TA. Extension in integrin activation of the α subunit leg at a Ca²⁺-dependent epitope in the thigh/genu interface. Proc. Natl. Acad. Sci. U.S.A. 2004. 101: 15422-15427.

Chen JF, Takagi J, Xie C, Xiao T, Luo B-H, Springer TA. The relative influence of metal ion binding sites in the I-like domain and the interface with the hybrid domain on rolling and firm adhesion by integrin α₄β₇. J. Biol. Chem. 2004. 279: 55556-55561.

Shimaoka M, Xiao T, Liu J-H, Yang Y, Dong Y, Jun C-D, McCormack A, Zhang R, Joachimiak A, Takagi J, Wang J-H, Springer, TA. Structures of the αL I domain and its complex with ICAM-1 reveal a shape-shifting pathway for integrin regulation. Cell. 2003. 112: 99-111.

Shimaoka M, Lu C, Salas A, Xiao T, Takagi J, Springer TA. Stabilizing the integrin αM inserted domain in alternative conformations with a range of engineered disulfide bonds. Proc. Natl. Acad. Sci. U.S.A. 2002. 99:16737-16741.

Xiao T, Gardner KH, Sprang SR. Cosolvent-induced transformation of a death domain tertiary structure. Proc. Natl. Acad. Sci. U.S.A. 2002. 99: 11151-11156.

Special Interest Groups: Immunology, Structural Biology, X-ray Diffraction, Cell Biology

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