KH 04 Flashcards
What is the oil drop model?
In properly-folded proteins,
hydrophobic amino acid
side-chains are not exposed
at the surface, but are buried
in the core.
What can be a sign of misfolding in a protein?
Hydrophobic patches at the surface of a protein.
Who received the 1972 Nobel Prize in chemistry in 1972 and what did they receive it for?
Anfinsen for his work on ribonuclease. He showed that the 3D structure is determined by the amino acid sequence
Spontaneous refolding of a
denatured protein is thought to be
through a “_____ _____”.
folding pathway. Likewise for nascent proteins being
synthesized on ribosomes.
Proteins are synthesized sequentially
from the ______ to the _____.
N-terminus (amino terminus), C-terminus (carboxy terminus)
During protein synthesis, which terminal region starts to fold before the other terminal region is synthesized?
The N-terminal region folds before the C-terminal region is synthesized
What is the folding of many proteins facilitated by?
Chaperones
What are chaperones?
Chaperones are proteins that help guide protein folding along productive pathways, by permitting partially misfolded proteins to return to the proper folding pathway.
What do chaperones recognize?
Exposed hydrophobic patches
Many chaperones are upregulated under conditions where misfolded proteins accumulate. What is an example of a condition that misfolds proteins?
Heat-shoock
How do chaperones work?
Chaperones work through ATP-dependent cycles of binding to, and release from, misfolded “client” molecules, at exposed hydrophobic patches. By blocking the exposed hydrophobic patches the chaperone keeps the folding or refolding protein ‘out of trouble’, while productive folding events occur.
What can chaperones do?
Chaperones can fold newly made proteins into functional conformations, refold misfolded or unfolded proteins into functional conformations…..also disassemble potentially toxic protein aggregates that form due to protein misfolding, and assemble and dismantle large multiprotein complexes, and mediate transformations between inactive and active forms of some proteins.
What are the 2 major classes of chaperones?
- Molecular chaperones (operate as single molecules)
- Chaperonins (form a multisubunit “refolding” chamber)
What is an example of a major molecular chaperone that helps newly-synthesized proteins follow the correct
folding pathway?
Hsp70
What does Hsp stand for?
Heat Shock Protein
Chaperones work through a cycle of client protein binding and conformational change associated with _____ and _____.
ATP binding, hydrolysis
What is an example of a chaperonin?
Hsp60
How do chaperonins work?
They form an enclosed chamber made up of inward-facing protein-binding subunits that undergo concerted ATP-binding/hydrolysis and conformation change.
Why are molecular chaperones and chaperonins essential for life?
Because although some proteins can fold and refold on their own without any help, the majority of cellular proteins require their assistance to adopt the proper 3D structure.
What is an example of a protein that can fold and refold without any help?
Ribonuclease
How have molecular chaperones and chaperonins evolved through evolution?
Chaperones are very ancient (found in both eukaryotes and prokaryotes) and their amino acid sequence has been very highly conserved through evolution. If they had not evolved, the cell would have a crippling burden of misfolded nonfunctional and aggregate-prone proteins.
What happens to irretrievably misfloded proteins?
They are destroyed by proteolytic cleavage into small fragments.
What is the ubiquitin/proteasome system for protein degradation?
Step 1: Poly-ubiquitin “tags” damaged or misfolded proteins for degradation.
Step 2: Ubiquitin-tagged proteins are fed into a multisubunit chamber in which the subunits form inward-facing proteases.
What are ubiquitins?
76-residue proteins that can be covalently linked to lysine residues on target proteins.
