Williams, David B. - University of Toronto - Department of Biochemistry

个人简介

David Williams did his doctoral work with Harry Schachter at the University of Toronto in the area of glycoprotein biogenesis followed by postdoctoral studies at Johns Hopkins University with Bill Lennarz and Gerald Hart where he developed an interest in protein folding and quality control in the mammalian secretory pathway. As a principal investigator he discovered the calnexin chaperone system and has characterized it extensively. He has also made important contributions to the field of antigen presentation by class I histocompatibility molecules, particularly in how these molecules assemble with antigenic peptides in the endoplasmic reticulum. Current research focuses on the roles of molecular chaperones, protein disulfide isomerases and peptidyl prolyl isomerases in protein folding as well as in the quality control triage system of the endoplasmic reticulum. He has held several administrative positions within the Biochemistry Department including Acting Chair (1996-1997) and Graduate Coordinator (2001-2005). He was also elected President of the Canadian Society of Biochemistry, Molecular and Cellular Biology in 2009 and has served on the Medical Review Panel of the Gairdner Award Foundation from 2009 – 2013.

研究领域

Our research focuses on how proteins fold and assemble within the endoplasmic reticulum (ER), including the cellular machinery that monitors the integrity of this process. Protein folding within the ER is complex and highly coordinated, involving post-translational modifications such as Asn-linked glycosylation and disulfide bond formation as well as the acquisition of native tertiary and quaternary structure. Furthermore, the ER houses a sophisticated “quality control” system that monitors the folding status of a protein and retains misfolded conformers for eventual destruction by a process known as ER-associated degradation (ERAD). Many inherited human diseases such as cystic fibrosis involve ER retention and disposal of aberrant proteins. Since these proteins often retain a degree of function, there is intense interest in studying ER folding and quality control to learn how these processes may be manipulated in disease states to enhance trafficking of mutant proteins to their normal sites of action and improve function. Our efforts are directed toward characterizing major players in ER folding and quality control. These include several molecular chaperones, a variety of folding enzymes, as well as components of ERAD disposal pathways.

近期论文

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Contributions of the lectin and polypeptide binding sites of calreticulin to Its chaperone functions in vitro and in cells. Lum, R., Ahmad, S., Hong, S-J., Chapman, D.C., Kozlov, G. and Williams, D.B. J. Biol. Chem. 2016. 291(37):19631-41. Read Inhibition of the FKBP family of peptidyl prolyl isomerases induces abortive translocation and degradation of the cellular prion protein. Stocki, P., Sawicki, M., Mays, C. E., Hong, S. J., Chapman, D. C., Westaway, D. and Williams, D. B. Mol. Biol. Cell 2016. 27(5):757-767. Read Cyclophilin C participates in the US2-mediated degradation of major histocompatibility complex Class I molecules. Chapman, D. C., Stocki, P. and Williams, D.B. PLoS One. 2015. 10(12):e0145458. Read Depletion of cyclophilins B and C leads to dysregulation of endoplasmic reticulum redox homeostasis. Stocki P, Chapman DC, Beach LA, Williams DB J Biol Chem. 2014. 289(33):23086-96 Read Vitamin K epoxide reductase contributes to protein disulfide formation and redox homeostasis within the endoplasmic reticulum. Rutkevich LA, Williams DB. Mol Biol Cell. 2012. 23(11):2017-27 Read Structural and functional relationships between the lectin and arm domains of calreticulin. Pocanschi, C.L., Kozlov, G., Brockmeier, U., Brockmeier, A., Williams, D. B. and Gehring, K. J. Biol. Chem. 2011. 286: 27266-27277 Read Participation of lectin chaperones and thiol oxidoreductases in protein folding within the endoplasmic reticulum. Rutkevich, L.A. and Williams, D.B. Curr. Opin. Cell Biol. 2011. 23(2):157-166. Read Functional relationship between protein disulfide isomerase family members during the oxidative folding of human secretory proteins. Rutkevich, L. A., Cohen-Doyle, M. F., Brockmeier, U. and Williams, D. B. Mol. Biol. Cell 2010. 21: 3093-3105. Read