William R. Skach

M.D., Harvard Medical School, 1983
Associate Professor, Medicine

Abnormal protein folding is the underlying cause of a wide variety of human diseases that range from genetic disorders such as cystic fibrosis to acquired forms of cancer. Protein misfolding is particularly common in the endoplasmic reticulum (ER) where nearly one third of all cellular proteins are synthesized. Our laboratory is investigating two aspects of this problem. First, how does cellular machinery facilitate protein folding in the ER? And second, how are misfolded proteins recognized and directed into degradation pathways? To address these questions we are investigating the biogenesis and degradation of several model polytopic proteins including ABC transporters and aquaporin water channels. One project is focused on how the Sec61 complex facilitates translocation, orientation and integration of these proteins into the ER membrane. These studies use in vitro translation systems to incorporate photoactive crosslinking probes into nascent polypeptides and define critical interactions between nascent proteins and components of the ER translocation machinery at specific stages of protein synthesis. Related experiments will investigate how genetic mutations disrupt the folding pathway by altering such interactions. In a second project we are developing a proteomic approach to define the composition of protein complexes, e.g. cellular chaperones and related proteins, responsible for ubiquitination and degradation oF ER membrane proteins by the 26S proteasome.

We believe that understanding the machinery involved in ER quality control is a critical step in developing new therapies for protein folding disorders. Toward this end, projects in the laboratory are investigating how inherited mutations disrupt CFTR biogenesis in cystic fibrosis and aquaporin 2 biogenesis in nephrogenic diabetes insipidus. Additional areas of research involve the multidrug transporter, P-glycoprotein, a major cause of drug resistance in cancer. Through these studies we hope to gain insight into basic disease mechanisms and ultimately identify novel drug targets.

 

Recent publications:

Oberdorf, J., Carlson, E., Skach, W. Redundancy of mammalian proteasome b-subunit function during endoplasmic reticulum associated degradation. Biochemistry, 2001, In Press.

Lu, Y., Turnbull, I., Bragin, A., K, Carveth, Verkman, A., Skach, W. Topologic reorientation of Aquaporin-1 during maturation in the endoplasmic reticulum. Mol. Biol. Cell., 11:2973-2985, 2000

Foster, W., Helm, A., Turnbull, I., Gulati, H., Yang, B., Verkman, A., Skach, W. Identification of sequence determinants that direct alternate biogenesis pathways for aquaporin-1 and aquaporin-4. J. Biol. Chem. 275:34157-34165, 2000

Xiong, X., Chong, E., Skach, W. Evidence that ER associated degradation of CFTR is linked to retrograde translocation from the ER membrane. J. Biol. Chem. 274:2616-2624, 1999

Skach, W.R. Defects in Processing and Trafficking of CFTR. Kidney International, 57:825-831, 2000

Moss, K., Helm, A., Lu, Y., Bragin, A., Skach, W. Coupled translocation events generate topological heterogeneity at the ER membrane. Molecular Biology of the Cell. 9:2681-2697, 1998

To contact Dr. Skach directly: skachw@ohsu.edu