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William Skach, MD

Professor, Biochemistry & Molecular Biology
Admin Unit: SOM-Biochemistry & Molecular Biology Department
Phone: 4-7322
Lab Phone: 4-7315
Fax: 4-8393
Office: RJH 7375
Mail Code: L-224
Programs:
Biochemistry & Molecular Biology
Cell & Developmental Biology
Physiology & Pharmacology
Program in Molecular & Cellular Biosciences
Research Interests:
Human protein folding diseases, Cystic fibrosis pathogeneisis and treatment, Membrane protein biogenesis and degradation, Water channel (aquaporin) folding. Endoplasmic Reticulum associated degradation (ERAD). Role of Hsp70 chaperones in the ubiquitin proteasome pathway. » PubMed Listing
Preceptor Rotations
Dr. Skach has not indicated availability for preceptor rotations at this time.
Faculty Mentorship
Dr. Skach has not indicated availability as a mentor at this time.
Profile

WILLIAM SKACH M.D. 

PROFESSOR, BIOCHEMISTRY & MOLECULAR BIOLOGY

RESEARCH INTERESTS: CELLULAR AND BIOCHEMICAL BASIS OF HUMAN PROTEIN FOLDING DISORDERS: Pathogenesis of Cystic Fibrosis, Aquaporin biogenesis, Membrane protein folding.

Human protein folding disorders comprise a group of diverse clinical diseases that involve every organ system.  Despite this diversity, they share a common molecular pathology in which inherited mutations cause structural abnormalities that are recognized by cellular quality control machinery.  For example, cystic fibrosis is an autosomal recessive disease in which the mutant CFTR chloride channel fails to fold properly, is rapidly ubiquitinated in the endoplasmic reticulum (ER), and degraded by the 26S proteasome via a process known as ER Associated Degradation (ERAD).  Lack of CFTR in the lung leads to mucus dehydration, recurrent infection, inflammation, and ultimately death.  Similarly, mutations in aquaporin 2 disrupt folding of a key water channel in the kidney, but in this case the outcome is a severe life-threatening urinary concentration defect.  Our group is investigating three basic themes in the pathogenesis of these disorders: 1) How do proteins acquire secondary and tertiary structure cotranslationally as they are synthesized by the ribosome? 2) How do cellular chaperones of the ER and cytosol facilitate membrane protein folding?  3) How are misfolded proteins recognized by quality control machinery, extracted from the ER membrane, and delivered to the ubiquitin-proteasome system?

Our experimental strategies involve a combination of cell biological, biochemical, and biophysical approaches.  Proteins are typically expressed from engineered DNA templates in cell free systems that reconstitute early folding, processing and degradation events.  Synthetic amino-acyl tRNAs are then used to incorporate non-native amino acids and thereby define the molecular environment of these nascent polypeptides using native and denaturing PAGE, photocrosslinking, fluorescence resonance energy transfer (FRET), fluorescence quenching and other biochemical techniques. The long term goal of our work is to define novel pathways for membrane protein folding, identify biogenesis events that are disrupted by disease-related mutations, and understand how these defects are corrected by novel, clinical drug candidates.

Dr. Skach is accepting rotation students for 2011-2012.

EDUCATION

1979.  B.S.  Biochemistry & Biophysics. Oregon Sate University. Biochemistry

1979.  B.S.  Agronomic Crop Science.  Oregon Sate University. Biochemistry

1983.   M.D. Harvard Medical School

1983-1991.   Clinical Training. Internal Medicine, Hematology/Oncology, University of California San Francisco. 

1990-1994.   Postdoctoral Training. Cancer Research Institute and Department of Physiology, University of California San Francisco,

PROFESSIONAL EXPERIENCE

1986.            Clinic Physician, Friends of Shanta Bawhan, Jorpati, Nepal

1988.           Physician and Instructor, Freedom Medicine. Peshawar, Pakistan

1994-1998.  Assistant Professor of Molecular and Cellular Engineering, University of Pennsylvania

1998-2005.  Associate Professor of Medicine, Cell and Developmental Biology, and Physiology & Pharmacology, Oregon Health & Science University

2005-present.  Professor of Biochemistry & Molecular Biology, Oregon Health &  Science University

 

SELECTED RECENT PUBLICATIONS

Devaraneni P., Conti, B., Matsumura, Y., Yang, Z., Johnson, A., Skach, W.  Stepwise Insertion and Inversion of a Type II Signal Anchor Sequence in the Ribosome-Sec61 Translocon Complex. Cell. 146:134-47,  2011.

Matsumura, Y., David, L.,  Skach, W.  Role of Hsc70 Binding Cycle in CFTR Folding and Endoplasmic Reticulum Associated-Degradation.  Mol Biol Cell. Jun 22, 2011.

Khushoo A, Yang Z, Johnson A, Skach W.  Ligand-Driven Vectorial Folding of Ribosome-Bound Human CFTR NBD1.  Molecular Cell. 41:682-92, 2011.

Buck, T., Wagner, J., Grund, S., Skach, W.  A novel tripartite structural motif involved in aquaporin topogenesis, monomer folding, and tetramerization.  Nature Struct. Mol. Biol. 14:762-769, 2007

RECENT REVIEWS

Brodsky, J., Skach, W. Protein Folding and Quality Control in the Endoplasmic Reticulum: Recent Lessons from Yeast and Mammalian Cell Systems. Current Opinion in Cell Biology.  2011.

Skach W.  Cellular mechanisms of membrane protein folding.  Nature Struct. Mol. Biol. 16:606-612, 2009