Proteins are complex molecules performing a vast array of tasks within all living organisms. They function as enzymes, structural components, and signaling molecules, facilitating nearly every cellular process. For a protein to perform its role, it must achieve a specific three-dimensional shape through protein folding. This precise folding enables correct interaction with other molecules and biological functions. When a protein fails to fold correctly, it becomes a misfolded protein. These improperly shaped molecules can lose their intended function or acquire harmful properties.
Understanding Misfolded Proteins
Proteins are long chains of amino acids, linked in a specific sequence. This sequence dictates how the protein folds into its unique three-dimensional shape. The folding process involves the amino acid chain coiling and bending, forming structures like alpha-helices and beta-sheets, before assembling into a complex overall form. The final shape creates binding sites and active regions that enable the protein to perform its specialized task.
A misfolded protein deviates from this correct, functional structure. It assumes an incorrect or unstable conformation. Even a slight alteration in shape can render a protein non-functional, as its active sites or binding regions may no longer be properly exposed or aligned. These altered structures can also expose hydrophobic regions, leading to aggregation with other misfolded proteins.
Why Proteins Misfold
Proteins can misfold for several reasons, from intrinsic errors in their production to external environmental influences. Genetic mutations are a common cause, as changes in a gene’s DNA sequence can alter the protein’s amino acid sequence. A single amino acid substitution can disrupt the folding pathway, preventing the protein from achieving its correct shape.
Errors can also occur during protein synthesis. Ribosomes, the cellular machinery that builds proteins, can sometimes incorporate an incorrect amino acid or prematurely terminate synthesis. This leads to truncated or structurally flawed proteins unable to fold correctly. Even without genetic mutations or synthesis errors, the folding process can sometimes go awry by chance, resulting in a protein adopting a suboptimal conformation.
Environmental stressors further contribute to protein misfolding. Elevated temperatures can cause proteins to denature, losing their three-dimensional structure. Extreme changes in pH levels or exposure to oxidative stress can also damage protein structures and interfere with proper folding. These stressors can lead to a buildup of misfolded forms.
Cellular Responses to Misfolding
Cells possess sophisticated quality control systems to detect and manage misfolded proteins, preventing their accumulation. One primary defense involves chaperone proteins, molecules that assist in protein folding. These chaperones bind to newly synthesized or partially unfolded proteins, helping them achieve their correct three-dimensional conformation. Some chaperones can also help refold proteins denatured by stress.
When proteins are too severely misfolded to be salvaged, cells activate degradation pathways to remove them. The ubiquitin-proteasome system (UPS) is a pathway for targeted protein destruction. Misfolded proteins are tagged with ubiquitin, signaling their delivery to the proteasome. The proteasome disassembles ubiquitinated proteins into smaller peptides, which can then be recycled.
Another degradation pathway is autophagy, a cellular process that encapsulates cellular components, including misfolded protein aggregates, within autophagosomes. These then fuse with lysosomes, organelles containing digestive enzymes. The enzymes break down the enclosed material, clearing the cell of damaged or unwanted proteins and aggregates. These responses maintain protein homeostasis.
Misfolded Proteins and Disease
Failure of cellular quality control systems to manage misfolded proteins can lead to their accumulation, contributing to various human diseases. When misfolded proteins aggregate, they form insoluble clumps that disrupt cellular functions and become toxic. This aggregation is common in many neurodegenerative disorders, where progressive neuron loss leads to debilitating symptoms.
For example, Alzheimer’s disease is characterized by the accumulation of amyloid-beta peptides and tau proteins, which misfold and form plaques and tangles in the brain. Parkinson’s disease involves the misfolding and aggregation of alpha-synuclein protein into Lewy bodies. Huntington’s disease results from the misfolding of an abnormally expanded huntingtin protein, leading to neuronal degeneration. These protein aggregates can impair synaptic function, disrupt cellular transport, and ultimately lead to cell death.
Beyond neurodegenerative conditions, protein misfolding is implicated in other systemic diseases. Cystic fibrosis, for instance, is caused by mutations in the gene encoding the CFTR protein. Some mutant CFTR proteins are misfolded and prematurely degraded by the cell’s quality control system, leading to impaired chloride transport and mucus buildup. Prion diseases, such as Creutzfeldt-Jakob disease, involve a normal protein (PrPC) that can misfold into an infectious form (PrPSc) and induce other normal proteins to misfold, leading to rapidly progressive neurodegeneration.