Protein Folding Processes and Stages

The process where a linear polypeptide chain acquires its functional 3D structure.

The initial stage of protein folding, where the polypeptide chain is synthesized by the ribosome.

Local regions of the protein adopt repetitive structures like alpha-helices and beta-sheets through hydrogen bonding between backbone atoms.

Hydrophobic amino acids cluster together inside the protein, minimizing their contact with water. This creates a loosely packed hydrophobic core, leading to the molten globule state.

Water molecules are excluded from the hydrophobic core as the protein folds more tightly. This stabilizes the folding process and minimizes the energy cost of exposing hydrophobic residues to water.

Independent folding units called 'domains' interact and arrange themselves relative to each other. This guides the formation of the functional 3D structure.

The protein reaches its final 3D structure by tightly packing side chains in the hydrophobic core and optimizing weak interactions like hydrogen bonds, van der Waals forces, and ionic interactions.

The protein achieves its most thermodynamically stable configuration.

Proteins with multiple polypeptide chains (subunits) that assemble into a functional complex.

Interactions like hydrophobic contacts, hydrogen bonds, and ionic interactions that hold subunits together in quaternary structure.

Molecules that help proteins fold correctly by preventing aggregation and ensuring the right structure.

Also known as Heat Shock Proteins (HSPs), they are produced in response to stress like heat, and assist proteins in achieving their correct conformation.

The sterically allowed regions on Ramachandran plots that predict favorable backbone conformations of amino acids during folding.

A small amino acid with high flexibility due to its lack of a side chain, allowing it to occupy regions on Ramachandran plots others cannot.

A rigid, cyclic amino acid that restricts its backbone flexibility. It's known for breaking alpha-helices.

A non-protein molecule that is permanently associated with a protein. Often essential for function, like heme in hemoglobin.

A specialized chaperone that interacts with newly synthesized proteins entering the ER lumen, preventing aggregation and ensuring proper folding.

A chaperone that binds calcium ions and interacts with carbohydrate modifications on proteins, ensuring proper folding and quality control.

A chaperone that specifically stabilizes alpha-globin chains in the absence of beta-globin chains during hemoglobin assembly.

The accumulation and aggregation of free alpha-globin chains in the absence of beta-globin chains, leading to potential toxicity for the cell.

A non-functional hemoglobin variant associated with severe anemia, caused by the accumulation of alpha-globin chains in the absence of beta-globin chains.

A cellular mechanism for targeted protein degradation, critical for maintaining protein homeostasis and regulating various biological processes.

A process where proteins are targeted for degradation by attaching a polyubiquitin chain to them.

A large protein complex responsible for degrading polyubiquitinated proteins into peptide fragments.

A group of diseases caused by the buildup of insoluble amyloid fibrils in tissues and organs. These fibrils are formed by misfolded proteins that aggregate into beta-pleated sheet structures.

Amyloid fibrils are formed from misfolded proteins that aggregate into beta-pleated sheet structures.

Amyloid formation can be a potential folding state for all proteins. However, under normal conditions, chaperones prevent proteins from adopting this conformation.

Misfolding occurs when hydrophobic fragments of a protein, usually hidden inside, get exposed to the watery environment. This increases the protein's tendency to aggregate.

Misfolded protein intermediates form oligomeric beta-sheet structures, which then grow into protofibrils and finally cross-beta amyloid-like fibrils.

The stability of amyloid fibrils is mainly due to hydrogen bonding between beta-sheets. The amino acid side chains don't play a major role in their stability.

The brain is sensitive to amyloid buildup, showing noticeable symptoms early on due to its complexity. Even a small amount of amyloid can cause significant neurological damage.

Organs like the liver and heart can tolerate amyloid accumulation for a while before symptoms appear. Substantial deposits may go unnoticed until significant damage occurs.

A protein found in the brain that is the main component of amyloid plaques in Alzheimer's disease. It forms a fibrous structure through aggregation and has a length of 40-42 amino acids.

Neurofibrillary tangles are formed by the aggregation of an abnormal form of a protein called tau, which becomes tangled and disrupts microtubule structure. This leads to dysfunction and death of neurons.

Amyloid plaques and neurofibrillary tangles are both critical features found in the brains of Alzheimer's disease patients.

The amyloid precursor protein is a transmembrane protein present on the surface of neurons and other tissues. It plays a role in neural repair and development.

Amyloid beta is derived from the amyloid precursor protein (APP) through a series of enzymatic cleavages. These cleavages release amyloid beta, which can then aggregate and form plaques.

An abnormal form of tau protein is associated with the formation of neurofibrillary tangles in Alzheimer's disease. This abnormal tau inhibits the function of its normal form, which normally helps in microtubule assembly.

While the majority of Alzheimer's disease cases are sporadic (not inherited), around 5-10% are familial, meaning they are linked to genetic mutations in specific genes.

While amyloid plaques and neurofibrillary tangles are key features of Alzheimer's disease, they are not the only factors involved. Other factors, such as inflammation and oxidative stress, also contribute to the disease's progression.

A type of misfolded protein that accumulates in the brain in Parkinson's Disease, disrupting neuronal function.

Prion diseases are caused by misfolded forms of the prion protein, which convert normal prion proteins into the misfolded state, leading to aggregation and neurodegeneration.

Amylin, a hormone associated with insulin secretion, forms amyloid deposits in the pancreas, disrupting insulin production and contributing to beta-cell death.

Fatal Familial Insomnia (FFI) is characterized by prion aggregates in specific brain regions, leading to sleep disturbances and neurodegeneration. It's caused by a genetic mutation in the PRNP gene, altering the folding of the prion protein.

Primary amyloidosis, also known as AL amyloidosis, involves the accumulation of amyloid fibrils formed from misfolded light chains of immunoglobulins, primarily affecting organs like the heart, kidney, and liver.

Hereditary Transthyretin Amyloidosis (ATTR) is caused by mutations in the TTR gene, leading to misfolding of the transthyretin protein and formation of amyloid fibrils.

Different proteins can misfold and aggregate into amyloid fibrils causing various diseases.