Course Meeting Times
Lectures: 1 session / week, 2 hours / session
Prerequisites
Recommended prerequisites are:
7.03 Genetics
7.05 General Biochemistry
7.06 Cell Biology
7.28 Molecular Biology
Course Description
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.
Format
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.
Grading
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.
Calendar
| WEEK # | TOPICS | KEY DATES |
|---|---|---|
| 1 | Introduction and Course Overview | |
| 2 | ER Quality Control and Degradation | |
| 3 | Discovery of Ubiquitin as a Tag for Proteasomal Degradation | |
| 4 | The Ubiquitin Conjugation Cascade | |
| 5 | Biology Seminar, Proteotoxicity of β-aggregation: Mechanisms and defense by molecular chaperones. Harvard Medical School, Boston. Speaker: Dr. F. Ulrich Hartl from Max Planck Institute of Biochemistry, Germany | |
| 6 | Biochemical Approaches to Measure Protein Dislocation | |
| 7 | The Putative Dislocon: Lessons from Yeast and Mammalian Systems | |
| 8 | Substrate Recognition: The Glycan Destruction Signal for ERAD | Midterm Assignment is due |
| 9 | Cytosolic Regulation of Misfolded/Mislocalized Protein Degradation | |
| 10 | Viral Avoidance and Exploitation of the Ubiquitin Proteasome System | |
| 11 | Toxin Invasion through the ERAD Machinery | |
| 12 | Student Oral Presentations | Student Oral Presentations |
| 13 | ER-associated Degradation in Disease |