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Research Description

Proteins that span the membrane multiple times (polytopic proteins) comprise a diverse group of proteins that includes membrane receptors, transporters, ion channels and enzymes. In the past two decades a great deal has been learned regarding how such proteins function. Little is known, however, of the details regarding their assembly into membranes and specific steps involved in intracellular maturation, processing and degradation. Research in the Skach laboratory is centered around two basic issues relating to polytopic protein biology. The first is the mechanism by which such proteins translocate across, fold into and assemble within in the endoplasmic reticulum membrane. The second is the mechanism by which disease related mutations disrupt protein folding, alert quality control machinery and direct protein degradation via the ubiquitin-proteasome pathway.

William Skach

William Skach, MD

Professor of Biochemistry & Molecular Biology

Dr. Skach received his BS in Biochemistry and Biophysics from Oregon State University in 1979 and his MD Degree from Harvard Medical School in 1983. He completed clinical training in Internal Medicine, Hematology and Oncology at University of California, San Francisco and then undertook postdoctoral studies with Vishwanath Lingappa, also at UCSF. He started his laboratory at the University of Pennsylvania and moved to OHSU in 1998.

Department of Biochemistry and Molecular Biology
Oregon Health & Science University
3181 SW Sam Jackson Park Road
Portland, Oregon 97239
Phone: 503-494-7315
Fax: 503-494-8393
Email: skachw@ohsu.edu

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Research Interests

  1. Biogenesis of polytopic integral membrane proteins
  2. Mechanisms of protein translocation and assembly in the endoplasmic reticulum
  3. ER quality control and ER-associated degradation (ERAD)
  4. Extraction and Degradation of polytopic membrane proteins

Current Projects

  1. Molecular pathogenesis of cystic fibrosis.
    • Role of Sec61 translocation machinery in CFTR biogenesis.
    • Cotranslational CFTR folding analyzed by Fluorescence Resonance Energy Transfer (FRET)
    • Mechanism of CFTR extraction and ER Associated Degradation (ERAD)
    • Effect of CF mutations on CFTR Folding and trafficking
  2. Aquaporin biogenesis and transmembrane assembly.
    • Molecular characterization of aquaporin folding pathways
    • Identification of sequence determinants that direct aquaporin topology in the ER
    • Photocrosslinking analysis of Sec61-Aquaporin interactions
  3. Sec61 translocon function
    • Role of the ribosome translocon junction in membrane protein topogenesis
    • Mechanisms of Sec61-mediated membrane integration
    • Chaperoning role of the ER Translocon in membrane protein folding

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Translocation Animations

Protein translocation and biogenesis in the ER is a dynamic process that involves the coordinated function of complex machinery. For polytopic proteins this process involves multiple rounds of translocation initiation and termination, proper orientation of TM segments within respect to the membrane, and integration of TM helices into the lipid bilayer. All of these events must occur without mixing of ER lumenal and cytosolic components. We have generated several crude animations using Macromedia Flash to illustrate how these events can be carried out by ER translocation machinery.

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