Proteins are complex molecules composed of amino acids, linked in long chains. For a protein to perform its specific job, this linear chain of amino acids must fold into a precise three-dimensional shape. Protein misfolding occurs when a protein fails to achieve or maintain this correct structure, which can disrupt its normal function or lead to harmful effects within the cell.
The Role of Proper Protein Folding
A protein’s specific three-dimensional shape is fundamental to its function, as this unique structure dictates how it interacts with other molecules, catalyzes reactions, or provides structural support. Enzymes, for instance, are proteins whose precise shapes allow them to bind to specific molecules and accelerate biochemical reactions. Structural proteins like collagen and keratin form intricate networks that provide strength and flexibility to tissues.
The journey from a linear chain of amino acids to a functional, folded protein is a complex and highly regulated process. This process, known as protein folding, involves interactions between the amino acids, guided by their chemical properties. The correct folding ensures the protein can perform its designated role, while any deviation from this specific shape can compromise its activity or lead to dysfunction.
Genetic Predispositions
Errors in an organism’s genetic code, specifically DNA mutations, represent a significant cause of protein misfolding. These mutations can alter the sequence of amino acids that make up a protein, which can prevent it from folding correctly or make it unstable. A single change in a DNA nucleotide, known as a missense mutation, can result in the substitution of one amino acid for another in the protein chain.
Even a single amino acid change can profoundly affect a protein’s structure and function. For example, in sickle cell anemia, a single point mutation replaces glutamic acid with valine in the beta-globin chain of hemoglobin. This seemingly minor alteration causes hemoglobin molecules to misfold and aggregate, distorting red blood cells into a sickle shape and impairing their ability to carry oxygen effectively. Similarly, mutations in beta-crystallin proteins can destabilize them, increasing their tendency to clump together and cause cataracts.
Some genetic variations, previously considered “silent” mutations because they do not change the amino acid sequence, have also been shown to impact protein folding. These “synonymous” mutations can affect the rate at which ribosomes synthesize proteins, which can subtly alter how the protein folds and ultimately impair cellular function.
Environmental and Cellular Stressors
Beyond genetic factors, various external and internal conditions can induce or worsen protein misfolding. Environmental stressors, such as extreme temperatures, can directly disrupt the delicate balance of forces that maintain a protein’s proper shape. For instance, exposure to high heat can cause proteins to unfold, a process known as denaturation, leading to a loss of their normal structure and function.
Changes in pH, the acidity or alkalinity of the cellular environment, also impact protein folding by altering the electrical charges on amino acids, which are involved in forming the protein’s three-dimensional structure. Exposure to toxins or heavy metals can interfere with folding processes, sometimes by binding to specific sites on proteins and preventing them from achieving their correct conformation.
Cellular stressors, such as oxidative stress, also contribute to protein misfolding. Oxidative stress occurs when there is an imbalance between the production of reactive oxygen species (free radicals) and the cell’s ability to neutralize them with antioxidants. These reactive species can directly damage amino acids within proteins, leading to their misfolding, aggregation, and loss of function. Nutrient deprivation can also disrupt the cellular machinery necessary for proper protein synthesis and folding, further contributing to misfolding events.
Failures in Cellular Quality Control
Cells possess sophisticated internal mechanisms to ensure proteins fold correctly and to manage those that do not. Molecular chaperones are a class of proteins that assist in the proper folding of newly synthesized proteins and can help refold proteins that have become partially denatured. These chaperones bind to unstable or misfolded protein intermediates, preventing them from clumping together and guiding them towards their correct three-dimensional structure.
When proteins are irreversibly misfolded or damaged, cells activate degradation pathways to remove them. The ubiquitin-proteasome system (UPS) is a major pathway responsible for degrading most short-lived and misfolded proteins within the cell. In this system, misfolded proteins are tagged with a small protein called ubiquitin, which marks them for destruction by the proteasome, a large protein complex that breaks them down into smaller peptides.
Another cellular cleaning system is autophagy, a process where cells break down and recycle their own components, including misfolded protein aggregates. Autophagy involves the formation of double-membraned vesicles called autophagosomes that engulf cellular material, including misfolded proteins, and deliver them to lysosomes for degradation.
When these quality control systems are overwhelmed, malfunction, or become less efficient, for example due to aging or disease, misfolded proteins can accumulate, leading to cellular dysfunction and potentially cell death.
Prion-Induced Misfolding
A distinct and infectious cause of protein misfolding involves prions. Prions are unique because they are misfolded proteins that can induce normally folded versions of the same protein to also misfold into an abnormal, disease-causing conformation. This self-propagating nature means that the abnormal prion protein acts as a template, converting healthy proteins into more misfolded prions.
The most well-known prion protein is PrP, which in its normal cellular form (PrPC) is rich in alpha-helical structures. When it misfolds into the pathogenic scrapie form (PrPSc), it adopts a structure with a higher proportion of beta-sheets, making it resistant to degradation by cellular enzymes. This resistance leads to the accumulation of insoluble aggregates, particularly in the brain, causing damage and cell death. Prion diseases, such as Creutzfeldt-Jakob disease in humans and bovine spongiform encephalopathy in cattle, are progressive, untreatable, and invariably fatal neurodegenerative disorders.