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Questions and Answers
What is the primary component of amyloid plaques in Alzheimer’s disease?
What is the primary component of amyloid plaques in Alzheimer’s disease?
How long may it take for amyloid accumulation, in the case of certain diseases, to impact health?
How long may it take for amyloid accumulation, in the case of certain diseases, to impact health?
What structural feature do Aβ peptides adopt when forming amyloid plaques?
What structural feature do Aβ peptides adopt when forming amyloid plaques?
Which protein is derived from the proteolytic cleavage of the amyloid precursor protein (APP)?
Which protein is derived from the proteolytic cleavage of the amyloid precursor protein (APP)?
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Which percentage of Alzheimer’s disease cases are familial and linked to genetic mutations?
Which percentage of Alzheimer’s disease cases are familial and linked to genetic mutations?
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What role does normal tau protein play in neuronal cells?
What role does normal tau protein play in neuronal cells?
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What is a key pathological feature of Alzheimer's disease concerning tau protein?
What is a key pathological feature of Alzheimer's disease concerning tau protein?
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What type of interactions are involved in the assembly of quaternary structure proteins?
What type of interactions are involved in the assembly of quaternary structure proteins?
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What do both extracellular Aβ plaques and intracellular tau tangles signify in Alzheimer's pathology?
What do both extracellular Aβ plaques and intracellular tau tangles signify in Alzheimer's pathology?
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Why is glycine unique among amino acids in terms of flexibility?
Why is glycine unique among amino acids in terms of flexibility?
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What role do molecular chaperones play during protein folding?
What role do molecular chaperones play during protein folding?
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What is a consequence of protein misfolding?
What is a consequence of protein misfolding?
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Which of the following cofactors is required for hemoglobin function?
Which of the following cofactors is required for hemoglobin function?
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What defines the sterically allowed regions in protein folding?
What defines the sterically allowed regions in protein folding?
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Which amino acid is known as a helix breaker in alpha-helices?
Which amino acid is known as a helix breaker in alpha-helices?
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What is often associated with diseases known as amyloidoses?
What is often associated with diseases known as amyloidoses?
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What initiates the formation of a compact intermediate during protein folding?
What initiates the formation of a compact intermediate during protein folding?
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Which stage of protein folding involves the ribosome synthesizing the polypeptide chain?
Which stage of protein folding involves the ribosome synthesizing the polypeptide chain?
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In which stage do local regions adopt alpha-helices and beta-sheets?
In which stage do local regions adopt alpha-helices and beta-sheets?
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What stabilizes the folding process by excluding water molecules from the hydrophobic interior?
What stabilizes the folding process by excluding water molecules from the hydrophobic interior?
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Which type of interactions are optimized in the final stage of protein folding?
Which type of interactions are optimized in the final stage of protein folding?
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What describes the interaction of distinct structural domains in a protein?
What describes the interaction of distinct structural domains in a protein?
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What characterizes the hydrophobic core formed during the folding of globular proteins?
What characterizes the hydrophobic core formed during the folding of globular proteins?
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What is the purpose of the tightly packed side chains in the hydrophobic core of a protein?
What is the purpose of the tightly packed side chains in the hydrophobic core of a protein?
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What characterizes amyloidosis?
What characterizes amyloidosis?
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What contributes to the formation of amyloid fibrils?
What contributes to the formation of amyloid fibrils?
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What is the primary role of Calnexin in protein processing?
What is the primary role of Calnexin in protein processing?
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Which component of the ubiquitin-proteasome system is responsible for activating ubiquitin?
Which component of the ubiquitin-proteasome system is responsible for activating ubiquitin?
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How do amyloid fibrils stabilize their structure?
How do amyloid fibrils stabilize their structure?
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What is a common outcome of amyloid accumulation in the brain?
What is a common outcome of amyloid accumulation in the brain?
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What does the Alpha Hemoglobin Stabilizing Protein (AHSP) specifically do?
What does the Alpha Hemoglobin Stabilizing Protein (AHSP) specifically do?
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What is a consequence of not having beta-globin chains in hemoglobin assembly?
What is a consequence of not having beta-globin chains in hemoglobin assembly?
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Which of the following best describes the latency period in amyloidosis symptoms?
Which of the following best describes the latency period in amyloidosis symptoms?
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What role do protein chaperones play in relation to amyloid formation?
What role do protein chaperones play in relation to amyloid formation?
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Which of the following correctly describes the structure of the 26S proteasome?
Which of the following correctly describes the structure of the 26S proteasome?
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Which statement about amyloid-forming proteins is true?
Which statement about amyloid-forming proteins is true?
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What is the function of ubiquitin in the UPS?
What is the function of ubiquitin in the UPS?
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How many ubiquitin molecules are required to tag a protein for degradation?
How many ubiquitin molecules are required to tag a protein for degradation?
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How do larger organs respond to amyloid accumulation compared to the brain?
How do larger organs respond to amyloid accumulation compared to the brain?
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Which enzyme in the UPS is crucial for ensuring specificity in identifying target proteins?
Which enzyme in the UPS is crucial for ensuring specificity in identifying target proteins?
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What is the primary protein involved in Parkinson's disease and its pathological mechanism?
What is the primary protein involved in Parkinson's disease and its pathological mechanism?
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Which condition is characterized by the accumulation of amyloid fibrils due to misfolded immunoglobulin light chains?
Which condition is characterized by the accumulation of amyloid fibrils due to misfolded immunoglobulin light chains?
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What abnormal structural change occurs in the prion protein associated with Creutzfeldt-Jakob Disease?
What abnormal structural change occurs in the prion protein associated with Creutzfeldt-Jakob Disease?
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Which protein is implicated in Type 2 Diabetes Mellitus through its aggregation within pancreatic islets?
Which protein is implicated in Type 2 Diabetes Mellitus through its aggregation within pancreatic islets?
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Which condition shares a similar pathogenic mechanism with Creutzfeldt-Jakob Disease involving prion aggregates?
Which condition shares a similar pathogenic mechanism with Creutzfeldt-Jakob Disease involving prion aggregates?
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What causes the misfolding of Transthyretin in Hereditary Transthyretin Amyloidosis?
What causes the misfolding of Transthyretin in Hereditary Transthyretin Amyloidosis?
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Which type of amyloidosis is primarily associated with the overproduction of monoclonal light chains?
Which type of amyloidosis is primarily associated with the overproduction of monoclonal light chains?
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Which of the following diseases is characterized by the presence of amyloid fibrils leading to transmissible spongiform encephalopathy?
Which of the following diseases is characterized by the presence of amyloid fibrils leading to transmissible spongiform encephalopathy?
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Study Notes
Globular Protein Folding
- Protein folding is a highly ordered process where a linear polypeptide chain forms a functional 3D structure.
- This process involves 7 stages, each contributing to the stable conformation.
Protein Folding Stages
- 1. Translation: The ribosome synthesizes the polypeptide chain by linking amino acids according to the mRNA sequence. The chain begins as an unstructured, linear structure.
- 2. Secondary Structure Formation: Local regions of the protein fold into repeating structural motifs like alpha-helices and beta-sheets via hydrogen bonds between backbone atoms. This provides the initial framework for folding.
- 3. Hydrophobic Collapse: Hydrophobic amino acid side chains aggregate and bury themselves inside the protein, minimizing their exposure to water. This creates a hydrophobic core and forms a compact intermediate called the molten globule state.
- 4. Water Exclusion and Core Formation: Water molecules are excluded from the hydrophobic interior as the protein folds more tightly, minimizing the energy cost of exposing hydrophobic residues to water.
- 5. Domain Interactions: Distinct structural domains of the protein interact and position themselves relative to one another, guiding the formation of the final 3° structure.
- 6. Internal Packing: Side chains in the hydrophobic core are tightly packed, optimizing weak interactions like hydrogen bonds, van der Waals forces, and ionic interactions. This stage locks the protein into its most thermodynamically stable configuration.
- 7. Quaternary Structure Assembly (if applicable): Multiple polypeptide chains (subunits) assemble into a functional multimeric complex through interactions such as hydrophobic contacts, hydrogen bonding, and ionic interactions.
Important Considerations in Protein Folding
- Cofactor Interactions: Some proteins require cofactors, such as heme groups or metal ions, for proper folding and function.
- Phi/Psi Angles: Protein folding follows sterically allowed regions of Ramachandran plots, predicting favorable backbone conformations for amino acid residues. Glycine is highly flexible, while proline restricts backbone flexibility.
- Molecular Chaperones: Specialized chaperones assist in protein folding by preventing aggregation and ensuring correct structure formation. These chaperones (e.g., Hsp70, Hsp60/10, Hsp90) play different roles during folding, with Hsp70 helping during translation, Hsp60/10 helping within an organelle, and Hsp90 assisting with a varied range of proteins
- Folding Challenges: Protein misfolding can lead to aggregation and the formation of insoluble structures, causing diseases like amyloidoses (e.g., Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease). A misfolded protein PrP forms the basis of prion diseases.
Ubiquitin-Proteasome System (UPS)
- The UPS is a cellular mechanism for targeted protein degradation, maintaining protein homeostasis.
- Ubiquitination: Proteins destined for degradation are tagged with a polyubiquitin chain (requiring at least 4 ubiquitin molecules), using E1 (activating), E2 (conjugating), and E3 (ligase) enzymes.
- Proteasome Recognition & Degradation: Polyubiquitinated proteins are recognized by the alpha subunits of the 26S proteasome, and the beta subunits carry out proteolysis to break down the protein.
- Structure of the 26S Proteasome: The proteasome consists of a 20S core particle and 19S regulatory particles, with specific alpha and beta subunits for proteolytic activity and recognizing ubiquitinated proteins.
- Ubiquitin Recycling: Ubiquitin is recycled to reuse for further tagging.
Amyloidosis
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Amyloidosis is a group of disorders characterized by the abnormal deposition of insoluble amyloid fibrils in tissues and organs.
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These fibrils form from misfolded proteins that aggregate into B-pleated sheet structures via hydrogen bonding, leading to damage & dysfunction.
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Stages of Amyloid Formation:
- Misfolding: Occurs when hydrophobic fragments of a protein (usually buried in the core) are exposed to the aqueous environment.
- Oligomerization and Fibril Formation: Misfolded proteins aggregate into oligomeric structures, growing to form protofibrils and finally cross-ß-amyloid fibrils.
- Stabilization: Amyloid fibrils are stabilized by hydrogen bonding.
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Amyloid formation can occur in different organs (including the brain), causing various symptoms, some of which can be delayed.
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Abnormal proteins involved in amyloidoses include misfolded immunoglobulin light chains, mutated transthyretin, altered prion protein, and Amyloid-beta peptides, amongst others.
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Description
Explore the intricate stages of globular protein folding, from translation to core formation. This quiz covers the seven crucial stages that lead to a functional 3D structure of proteins. Test your understanding of how proteins achieve their stable conformations.
