Proteins are the microscopic machinery responsible for nearly every task within our cells. For a protein to function, it must fold into a precise three-dimensional shape. If this structure is altered, the protein can no longer work correctly, much like a bent key fails to open its lock. When this delicate folding process goes wrong, it can have serious consequences for the cell and the entire organism.
What Causes a Protein to Unfold?
A protein’s intricate structure can be disrupted by various stressors, causing it to lose its shape in a process called denaturation. For instance, high temperatures can give the protein’s atoms too much energy, causing them to vibrate and break the bonds holding the folded structure together. This is demonstrated when cooking an egg, as heat denatures the albumin protein, turning the egg white opaque and solid. Changes in pH can also disrupt a protein’s shape by altering the electrical charges on its amino acids.
Stressors within the cell can also lead to protein unfolding. Oxidative stress, an imbalance of reactive oxygen molecules, can damage proteins and cause them to misfold. A lack of nutrients or energy can disrupt the protein production process, leading to errors. Furthermore, a protein’s stability is determined by its genetic blueprint. A gene mutation can change the sequence of amino acids, making the resulting protein unstable and prone to unfolding.
The Cellular Response to Unfolded Proteins
Cells possess a quality control system to manage unfolded proteins, known as the Unfolded Protein Response (UPR). This response is centered in the endoplasmic reticulum (ER), the cell’s main protein-folding factory. When the ER detects a buildup of unfolded proteins, a condition called ER stress, it activates the UPR to restore balance. The UPR is a signaling pathway designed to protect the cell from the toxic effects of these damaged proteins.
The UPR operates with three main objectives. First, it temporarily halts the production of new proteins to reduce the workload on the folding machinery. This pause gives the cell time to address the existing backlog of unfolded proteins without new ones adding to the problem.
The UPR also boosts the production of molecules to help fix the problem. It increases the synthesis of molecular chaperones, which bind to unfolded proteins and attempt to guide them back into their correct shape. If refolding is successful, the protein can perform its function. If a protein is too damaged to be repaired, the UPR initiates a disposal process where the protein is sent to the proteasome to be broken down for reuse.
Consequences of Protein Misfolding and Aggregation
When the Unfolded Protein Response is overwhelmed or fails to resolve the issue, the consequences for the cell can be severe. Unfolded proteins have exposed “sticky” surfaces that are normally tucked away inside their structure. These sticky patches cause the damaged proteins to clump together, forming clusters known as aggregates.
The formation of these protein aggregates can be toxic to the cell. These clumps can interfere with cellular processes, disrupt the function of other proteins, and impair organelles. For example, aggregates can block cellular transport pathways or sequester important molecules. The accumulation of these aggregates can trigger programmed cell death, or apoptosis, as the cell sacrifices itself to prevent damage to surrounding tissue.
The severity of a disease often correlates with the amount of aggregated protein in the cells. These aggregates place a burden on the cell’s clearance machinery, like the proteasomes. Once the rate of aggregation surpasses the cell’s capacity for clearance, the toxic accumulation can lead to widespread cell death and tissue damage.
Link to Human Diseases
The accumulation of misfolded and aggregated proteins is a hallmark of many human diseases, particularly neurodegenerative disorders. In Alzheimer’s disease, misfolded amyloid-beta proteins form plaques outside of neurons, while abnormal tau proteins form tangles inside them. Both disrupt communication and lead to cell death. Parkinson’s disease is characterized by the aggregation of alpha-synuclein into Lewy bodies within neurons, associated with the loss of dopamine-producing cells.
Aggregation is not the only way misfolded proteins cause disease. In cystic fibrosis, a mutation causes the CFTR protein to misfold. The cell’s quality control system recognizes the protein and targets it for destruction before it can reach the cell surface to perform its function. This loss of function leads to the thick, sticky mucus characteristic of the disease.
A unique mechanism is seen in prion diseases, such as Creutzfeldt-Jakob disease. In these conditions, a misfolded prion protein acts as a template, inducing normally folded proteins to adopt the same abnormal shape. This triggers a chain reaction that results in the rapid accumulation of toxic protein aggregates and severe brain damage. This templated conversion is a transmissible form of protein misfolding disease.