Curriculum
Module 03 · 75 min
Protein Structure, Folding & Quality Control
From Anfinsen's dogma to chaperones, the UPS, and the unfolded-protein response.
CoreClinicalResearch
Topics
What this module covers
- 01Levels of structure; Ramachandran constraints; intrinsically disordered proteins
- 02Folding landscapes, kinetic traps, and chaperone-assisted folding (Hsp70, Hsp90, TRiC, GroEL)
- 03Co-translational folding and ribosome-associated chaperones
- 04Ubiquitin-proteasome system: E1/E2/E3, polyubiquitin chain types
- 05Autophagy: macro-, micro-, chaperone-mediated; LC3 lipidation
- 06ER unfolded-protein response: PERK, IRE1, ATF6 arms
- 07Targeted protein degradation: PROTACs, molecular glues
Deep dives
Lesson sub-pages
Learning objectives
By the end of this module you will be able to
- L01Predict, given a misfolding mutation, which quality-control branch will engage and which clinical phenotype is plausible.
- L02Distinguish K48 from K63 polyubiquitin chains in cellular function.
- L03Explain how a PROTAC differs mechanistically from a competitive inhibitor.
Expected takeaways
What you should walk away believing
- →Most cellular proteins fold with chaperone help — Anfinsen's dogma is a special case, not the rule.
- →Proteostasis collapse is a unifying mechanism in neurodegeneration, ageing, and many cancers.
- →Drugging the degradation machinery (PROTACs, molecular glues) opens previously 'undruggable' targets.
Core summary
At the Core level
Proteins fold along energy landscapes shaped by their amino-acid sequence; the cell helps with chaperones, monitors with quality control, and disposes of failures with the proteasome or autophagy. When proteostasis fails — by mutation, age, or stress — proteins aggregate. Aggregation is not a passive end state; it is a signal that triggers stress responses, inflammation, and ultimately cell death.
Myth vs reality
Common misconception
Claim
AlphaFold has 'solved' protein structure.
Reality
AlphaFold predicts a single low-energy state of a single chain remarkably well. Conformational dynamics, complex assemblies, post-translational modifications, and disordered regions remain hard.
Evidence-graded claims
Claims, scored A–F
A
Proteasome inhibitors are first-line in multiple myeloma
Standard of care worldwide.
C
AlphaFold structures can be used directly for drug design
Useful for orientation; binding-pocket geometry often needs experimental refinement.
E
Heat-shock-protein induction extends human healthspan
Strong in worms/flies; unproven and oversold in humans.
Quiz
Check your understanding
Q1. Which polyubiquitin linkage canonically targets proteins for proteasomal degradation?
Q2. PROTACs work by:
Flashcards
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Front
Three arms of the ER UPR?
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Suggested reading
Primary literature
- Highly accurate protein structure prediction with AlphaFold — Jumper et al., Nature 2021 ↗
- Targeted protein degradation: from chemical biology to drug discovery — Békés et al., Nat Rev Drug Discov 2022 ↗