个人简介

B.A., 1970, Knox College Ph.D., 1975, University of Notre Dame NIH Postdoctoral Fellow, 1975–1977, Duke University Medical Center Established Investigator Award, American Heart Association, 1982–1987; Basic Science Research Award, University of South Carolina School of Medicine, 1990; Russell Research Award for Science, Mathematics, and Engineering, University of South Carolina, 2000; Carolina Trustee Professor Award, University of South Carolina, 2007; Elected Fellow, American Association for the Advancement of Science, 2010; South Carolina Governor's Award for Excellence in Scientific Research, 2011.

研究领域

Biochemistry

Research Areas: Biochemistry; protein chemistry, protein engineering, and molecular biology; structure-function studies of proteins and enzymes of blood with emphasis on the human complement system. Our laboratory is studying the structure and function of a group of blood proteins which are components of the human "complement system." The complement system is composed of about 35 different proteins, enzymes, and regulatory molecules that interact to provide host defense against bacteria and other pathogenic organisms. One product of these interactions is C5b-9, a large protein complex composed of complement components C5b, C6, C7, C8 and C9. The C5b-9 complex is also referred to as the "membrane attack complex" (MAC) of complement because it forms a transmembrane pore on target cells. Formation of this pore disrupts membrane organization and contributes to bacterial cell killing. Assembly of the MAC is of biochemical interest because it occurs by a sequential, nonenzymatic mechanism and involves major hydrophilic to amphiphilic transitions by the constituent proteins. The binding interactions involved are complex and determined by distinct structural features on each protein. One goal of our lab is to identify those features. Current efforts are focused on the physical and structural characterization of human C8 and analysis of its interaction with the other MAC components. Human C8 is an unusual protein composed of three nonidentical subunits referred to as a , β and g. Through cDNA cloning and sequencing, we determined the complete amino acid sequence of C8 and gained valuable insight into how this protein functions. Specific roles for a and β have been identified and it appears that each subunit contains several different binding sites. We also determined that a, β and g are encoded in different genes. Genomic structures of a and β indicate these proteins share a close ancestral relationship to each other and to C6, C7 and C9. By contrast, g is a member of the "lipocalin" family of proteins, and its role in the complement system is unknown. Our study of human C8 utilizes the methods of modern biotechnology. All three subunits have been cloned and expressed as recombinant proteins in insect and mammalian cells. Truncated forms of a and β as well as full-length g have also been produced in E. coli and used to investigate the location and properties of key binding sites. Several regions have been identified as being important in interactions with other components of the MAC, and with membrane proteins that regulate MAC activity. We also recently determined the X-ray crystal structure of human C8, a very large (150 kDa) protein. The structure suggest that human MAC proteins use a mechanism of pore formation that is similar to one used by bacterial pore-foming proteins, i.e. the cytolysins. By further exploring these and other structure-function relationships within the MAC proteins we hope to gain a better understanding of MAC formation and function. Such information will be useful for developing inhibitors of the MAC and for engineering MAC analogues that could destroy undesirable cells, e.g. tumor cells.

近期论文

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Weiland, M., Qian, Y. and Sodetz, J.M., “Membrane Pore Formation by Human Complement: Functional Importance of the Transmembrane b-hairpin (TMH) Segments of C8a and C9”, Mol Immunol. 57, (2014): 310-316. Lovelace, L.L., Cooper, C.L., Sodetz, J.M. and Lebioda, L., ""Structure of Human C8 Protein Provides Mechanistic Insight into Membrane Pore Formation by Complement"", J. Biol. Chem. 286, (2011): 17585-17592. Slade, D.J., Lovelace, L.L., Chruszcz, M., Minor, W., Lebioda, L. and Sodetz, J.M., ""Crystal Structure of the MACPF Domain of Human Complement Protein C8a in Complex with the C8g Subunit."" J. Mol. Biol. 379 (2008): 331-342. Lovelace, L.L., Chiswell, B., Slade, D.J., Sodetz, J.M. and Ledioda, L. ""Crystal Structure of Complement Protein C8g in Complex with a Peptide Containing the C8g Binding Site on C8a: Implications for C8g Ligand Binding. ""Mol. Immunol. 45, (2008): 750-756. Chiswell, B., L.L. Lovelace, C. Brannen, E.A. Ortlund, L. Lebioda, J.M. Sodetz, ""Structural Features of the Ligand Binding Site on Human Complement Protein C8g: A Member of the Lipocalin Family"", Biochem. Biophys. Acta 1774, (2007): 637-644. Brannen, C.L. and J.M. Sodetz. “Incorporation of Human Complement C8 into the Membrane Attack Complex is Mediated by a Binding Site Located within the C8b MACPF Domain.” Mol. Immunol. 44 (2007): 960-965. Chiswell, B., D.J. Slade, and J.M. Sodetz. ""Binding of the Lipocalin C8g to Human Complement Protein C8a is Mediated by Loops Located at the Entrance to the C8g Ligand Binding Site."" Biochim. Biophys. Acta, 1764, (2006): 1518-1524. Slade, D. J., B. Chiswell, and J.M. Sodetz. “Functional Studies of the MACPF Domain of Human Complement Protein C8a Reveal Sites for Simultaneous Binding of C8b, C8g and C9.” Biochemistry 45, (2006): 5290-5296. Dijk, W.V., S. DoCarmo, E. Rassart, B. Dahlback, and J.M. Sodetz. “The Plasma Lipocalins a1-acid glycoprotein, Apolipoprotein D, Apolipoprotein M and Complement Protein C8γ. In Lipocalins, Åkerström,B., Borregaard, N., Flower, D. and Salier, J-P, Eds., Landes Bioscience/Eurekah, 140-166, Georgetown, TX, (2006). Lebioda, L and J. M. Sodetz. ""Human Complement Protein C8."" Structural Biology of the Complement System, D. Morikis, J. D. Lambris, Eds., CRC Press, 233-250, London, (2005). Scibek, J. J., M. E. Plumb, and J. M. Sodetz. “Binding of Human Complement C8 to C9: Role of the N-Terminal Modules in the C8a Subunit.” Biochemistry 41, (2002): 14546-14551. Parker, C. L., and J. M. Sodetz. “Role of the Human C8 Subunits in Complement-Mediated Bacterial Killing: Evidence that C8g is not Essential.” Mol. Immunol. 39, (2002): 453-458. Musingarimi, P. and J. M. Sodetz. “Interaction between the C8a-g and C8b Subunits of Human Complement C8: Role of the C8b N-Terminal Thrombospondin Type 1 Module and Membrane Attack Complex/Perforin Domain.” Biochemistry 41, (2002): 11255-11260. Ortlund, E., C. L. Parker, S. F. Schreck, S. Ginell, W. Minor, J. M. Sodetz, and L. Lebioda. “Crystal Structure of Human Complement Protein C8g at 1.2Å Resolution Reveals a Lipocalin Fold and a Distinct Ligand Binding Site.” Biochemistry 41, (2002): 7030-7037. Plumb, M. E., and J. M. Sodetz. “An Indel Within the C8a Subunit of Human Complement C8 Mediates Intracellular Binding of C8g and Formation of C8a-g.""Biochemistry 39, (2000): 13078-13083. Schreck, S. F., C. P. Parker, M. E. Plumb, and J. M. Sodetz. “Human Complement Protein C8g.” BBA-Protein Structure and Molecular Enzymology (Special Issue on Lipocalins), J-P Salier; B. Akerstrom; and D. Flower, Eds., Biochim. Biophys. Acta. 1482, (2000): 199-208. Plumb, M. E., J. J. Scibek, T. D. Barber, R. J. Dunlap, P. L. Platteborze, and J. M. Sodetz. “Chimeric and Truncated Forms of Human Complement Protein C8a Reveal Binding Sites for C8b and C8g within the Membrane Attack Complex/Perforin Region.” Biochemistry 38, (1999): 8478-8484. Plumb, M. E., and J. M. Sodetz. “Proteins of the Membrane Attack Complex.” The Human Complement System in Health and Disease. J.E. Volanakis; M.M. Frank, Eds. M. Dekker, 119-148, New York, (1998).