Cellular garbage disposal: misfolded proteins in normal biology and human disease

Lectures: 1 session / week, 2 hours / session

Recommended prerequisites are:

7.03 Genetics
7.05 General Biochemistry
7.06 Cell Biology
7.28 Molecular Biology

The endoplasmic reticulum (ER) orchestrates different cellular processes by which proteins are synthesized, correctly folded, modified and ultimately transported to their final destinations. As part of this crucial biosynthetic process, proteins that are not properly folded and consequently detrimental to normal cellular function are constantly generated. A common signature of many neurodegenerative diseases, including Alzheimer's and Parkinson's, is accumulation and deposition of misfolded proteins that arise when the ability of cells to deal with the burden of misfolded proteins is compromised. In this course, we will explore how the ER quality control machinery ensures that only properly assembled proteins exit the ER while distinguishing between nascent proteins en route to their biologically active folded state from those that are terminally misfolded.

The flux through the ER involves a repertoire of proteins with varying physical characteristics, including soluble, membrane-bound and lipid-anchored proteins. We will discuss how such distinct cargo proteins are recognized, transported from the ER to the cytosol and ultimately degraded by proteasomes. Tools and approaches used to delineate underlying molecular mechanisms of the pathway, emerging concepts of specificity regarding substrate selection, possible modes of transport across the ER bilayer, maintenance in a soluble form once in the cytosol and the role of ubiquitylation in proteasomal degradation will be addressed.

This course is one of many Advanced Undergraduate Seminars offered by the Biology Department at MIT. These seminars are tailored for students with an interest in using primary research literature to discuss and learn about current biological research in a highly interactive setting. Many instructors of the Advanced Undergraduate Seminars are postdoctoral scientists with a strong interest in teaching.

The course will meet weekly, and two original papers from the research literature will be discussed each week. Students are expected to read both papers in advance and to be prepared for a round-table discussion. The emphasis will be on critical reading of key papers in the field of protein misfolding and degradation, both at the data and conceptual levels. At the end of each session, the instructor will present an introduction to the topic of the following week's assigned reading.

This course is graded pass/fail. The grading will be based on regular participation in the weekly meetings as well as on the two assignments.

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