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C. James McKnight, Ph.D.Associate Professor of Physiology and BiophysicsB.S. Washington College
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Research
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Recent PublicationsJiang, Z.H., Gantz, D., Bullitt, E., & McKnight, C.J., "Defining lipid interacting domains in the N-terminal region of apolipoprotein B," Biochemistry, 2006, in press. Jiang, Z.H. & McKnight, C.J. "A phosphorylation induced change in dematin headpiece," Structure, 14, 379-387, 2006. [PubMed Abstract] Grey M.J., Tang Y., Alexov E., McKnight C.J., Raleigh D.P., & Palmer AG III. "Characterizing a partially folded intermediate of the villin headpiece domain under non-denaturing conditions: Contribution of His41 to the pH-dependent stability of the N-terminal subdomain," J Mol Biol., 355, 1078-1094, 2006. [PubMed Abstract] Tang Y., Grey M.J., McKnight J., Palmer A.G. III, & Raleigh D.P. "Multistate folding of the villin headpiece domain," J Mol. Biol., 335, 1066-107, 2006. [PubMed Abstract] McKnight, C.J. & Cordes, M.J.H., "Networking at the Protein Society Meeting," Nature Chem. Biol.,1, 239-242, 2005. [PubMed Abstract] Meng, J., Vardar, D., Wang, Y., Guo, H.-C., Head, J.F. & McKnight, C.J. "The high resolution crystal structures of villin headpiece and mutants with reduced F-actin binding activity," Biochemistry, 44, 11963-73, 2005. [PubMed Abstract] Jiang, Z., Carraway, M. & McKnight, C.J., "Limited proteolysis and biophysical characterization of the lipovitellin homology region in apolipoprotein B," Biochemistry , 44, 1163-1173, 2005. [PubMed Abstract] Frank, B. S., Vardar, D., Chishti, A. H. & McKnight, C. J., "The NMR structure of dematin headpiece reveals a dynamic loop that is conformationally altered upon phosphorylation at a distal site." J Biol. Chem., 279, 7909-7916, 2004. [PubMed Abstract]. Burnett, J.R., Shan, J., Miskie, B.A., Hooper, A.J., Yuan, J., Tran, K., McKnight, C.J., Yao, Z., Hegel, R.A.,, "A novel non-truncating APOB gene mutation, R463W, causes familial hypobetalipoproteinemia," J. Biol. Chem., 278, 13442-13452, 2003. [PubMed Abstract] Wang, M., Tang, Y. Satoshi, S., Vugmeyster, L., McKnight, C.J. and Raleigh, D.P., "Dynamic NMR lineshape analysis demonstrates that the villin headpiece subdomain folds on the microsecond time scale," J. of the American Chemical Society, 125, 6032-3, 2003. [PubMed Abstract] Cordes, M.H.J., Walsh, N.P., McKnight, C.J., Sauer, R.T. , "Solution structure of switch Arc, a mutant with 3-10 helices replacing a wild-type beta-ribbon," J. Molecular Biology, 326, 899-909, 2003. [PubMed Abstract] L. Vugmeyster, O. Trott, C.J. McKnight, D.P. Raleigh, & A.G. Palmer III, "Temperature dependent dynamics of the villin headpiece helical subdomain, an unusually small thermostable protein," J. Molecular Biology, 320, pp. 841-54, 2002. [PubMed Abstract] D.Vardar, A.H. Chishti, B.S. Frank, E.J. Luna, A.A. Noegel, S.W. Oh, M. Schleicher, & C.J. McKnight, "Villin-type headpiece domains show a wide range of F-actin-binding affinities," Cell Motil Cytoskeleton, 52, pp. 9-21, 2002. [PubMed Abstract] B.S. Frank, D. Vardar, D.A. Buckley, & C.J. McKnight, "The role of aromatic residues in the hydrophobic core of the villin headpiece subdomain," Protein Science, 11, pp. 680-7, 2002. [PubMed Abstract] J. Grogan, C.J. McKnight, R.F. Troxler, & F.G. Oppenheim, "Zinc and copper bind to unique sites of histatin 5," FEBS Letters, 491, pp. 76-80, 2001. [PubMed Abstract] H. Herscovitz, A. Derksen, M.T. Walsh, C.J. McKnight, D.L. Gantz, M. Hadzopoulou-Cladaras, V. Zannis, C. Curry, & D.M. Small, "The N-terminal 17% of apoB binds tightly and irreversibly to emulsions modeling nascent very low density lipoproteins," J. Lipid Research, 42, pp. 51-59, 2001. [PubMed Abstract] M.H.J. Cordes, R.E. Burton, N.P. Walsh, C.J. McKnight, & R.T. Sauer, "An evolutionary bridge to a new protein fold," Nature Structual Biology, 12, pp., 1129-1132, 2000. [PubMed Abstract] D. Vardar, D.A. Buckley, B.S. Frank, & C.J. McKnight, "NMR structure of an F-actin-binding "headpiece" motif from villin." J. Molecular Biology, 294, pp. 1299-1210, 1999. [PubMed Abstract] M.H.J. Cordes, N.P. Walsh, C.J. McKnight, & R.T. Sauer, "Evolution of a protein fold in vitro," Science, 284, pp. 325-327, 1999. [PubMed Abstract] C.J. McKnight, P.T. Matsudaira, & P.S. Kim, "NMR structure of the 35-residue villin headpiece subdomain," Nature Structural Biology, 4, pp. 180-184, 1997. [PubMed Abstract] C.J. McKnight, D.S. Doering, P.T. Matsudaira, & P.S. Kim, "A thermostable subdomain within villin headpiece," J. Molecular Biology, 260, pp.126-134, 1996. [PubMed Abstract] • To top | ||||||
Contact Us
Department of Physiology and Biophysics
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One focus in the lab centers on the intriguing, modular F-actin binding “headpiece” motif. The headpiece motif is a compact (~70 amino acid) domain localized at the extreme C-terminus of much larger “core” domains from several functionally diverse classes of actin-binding proteins. These headpiece-containing proteins include villin, supervillin, dematin, limatin and TalB, and their functions range from maintenance of the cytoskeleton and cell-cell adherens junctions, to potential roles in development. We are interested in determining the three dimensional structures of headpiece motifs and detailing their interaction with actin, their core domains, and regulatory kinases.
Another area of interest is the development of minimal length folded proteins to bridge the gap between experimental and computational approaches to protein folding. We have shown that headpiece domain of villin contains a "subdomain" of only 35 residues that folds to form a novel three helix structure. The villin subdomain is one of the shortest amino acid sequences to fold to a monomeric native state in the absence of disulfide bonds or bound metals/ligands. We are using a mutational approach to address the question of how this short sequence encodes the information for a fully folded protein.
LDL is the major cholesterol transporting lipoprotein, and high LDL levels are correleated with Arthelroscrosis. We are investigating the early events in the formation of LDL and VLDL particles within the cell. We have modelled the first 17% of ApoB (ApoB-17) onto the crystal structure lipovitellin, whose sequence is homologous the N-terminal region of ApoB. We then used our ApoB-17 model to dock to a model lipid emulsion particle. This is one possible model for nascent LDL particle formation. We have tested the lipovitellin-based model by limited proteolysis and have created a bank of constructs corresponding to the individual domains for further structural and biophysical study.
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