Proteins are the molecular machinery within our bodies, carrying out nearly all cellular functions, from catalyzing reactions to transporting molecules. For these tasks, a protein must fold into a precise three-dimensional shape. This structure dictates its ability to interact correctly with other molecules and perform its designated job. Occasionally, however, proteins fail to achieve this proper conformation, becoming “misfolded.” Proper protein structure is essential for biological processes and overall health.
Understanding Misfolded Proteins
Proteins are initially synthesized as linear chains of amino acids. This amino acid sequence, known as the primary structure, contains all the instructions for the protein to fold into its correct three-dimensional shape. The folding process involves various interactions between amino acids, such as hydrogen bonds and hydrophobic interactions.
This folding results in structures like alpha-helices and beta-sheets (secondary structures), which then arrange into an overall three-dimensional shape (tertiary structure). A protein’s exact 3D shape is essential for its biological function, allowing it to bind to particular molecules or fit into specific cellular compartments. A “misfolded protein” is one that has failed to achieve this correct 3D shape, or has adopted an abnormal or harmful conformation. Such a protein can either lose its intended function, becoming inactive, or it can acquire new, often toxic, properties.
Why Proteins Misfold
Several factors can disrupt protein folding, leading to misfolded proteins. Genetic mutations, which are changes in a gene’s DNA sequence, are one cause. These alterations can modify the amino acid sequence, making it difficult for the protein to fold into its correct shape. Even minor genetic changes can affect a protein’s final structure.
Cellular stress and environmental factors also contribute. Conditions like excessive heat, oxidative stress, or changes in pH can disrupt interactions that stabilize a protein’s correct fold. For instance, high temperatures can cause proteins to unfold.
Even without mutations or external stressors, cellular machinery can make errors during protein synthesis. These mistakes can result in a polypeptide chain with an incorrect sequence or structure prone to misfolding. The crowded cellular environment further complicates folding, increasing misfolding likelihood.
The Cell’s Protein Quality Control
Cells possess internal mechanisms to manage misfolded proteins, preventing their formation, assisting refolding, or eliminating them. These systems maintain protein homeostasis. Molecular chaperones act as “helper proteins,” assisting newly synthesized proteins in folding correctly and refolding those that have misfolded due to stress.
The Ubiquitin-Proteasome System (UPS) is a cellular pathway dedicated to degrading misfolded or damaged proteins. Ubiquitin acts as a “tag,” marking proteins for destruction. Once tagged, these misfolded proteins are recognized by the proteasome, a multi-protein complex. The proteasome then breaks down the tagged proteins into amino acid components, which can be reused by the cell.
The Unfolded Protein Response (UPR) is a stress response activated when misfolded proteins accumulate within the endoplasmic reticulum (ER). The UPR aims to restore cellular balance by activating pathways that reduce protein production, increase chaperone synthesis, and enhance misfolded protein degradation.
Misfolded Proteins and Human Health
When the cell’s protein quality control systems are overwhelmed or fail, misfolded proteins can accumulate, with consequences for human health. One outcome is “loss of function” diseases, where a misfolded protein is non-functional and often degraded. For example, in cystic fibrosis, a mutation causes the CFTR protein to misfold and be targeted for degradation, preventing proper chloride transport and leading to disease symptoms.
Beyond losing function, some misfolded proteins can become toxic, particularly by aggregating into insoluble deposits, often called amyloid fibrils or plaques. These aggregates can damage cells and tissues, contributing to various diseases. Neurodegenerative diseases are a group where protein aggregation is a defining feature. In Alzheimer’s disease, misfolded beta-amyloid proteins accumulate into plaques, and tau proteins form neurofibrillary tangles in the brain, leading to neuronal dysfunction and death.
Parkinson’s disease is characterized by alpha-synuclein protein aggregation into Lewy bodies, disrupting cellular processes and causing neuronal damage. Huntington’s disease involves the misfolding and aggregation of the huntingtin protein, contributing to neuronal dysfunction and death. These protein aggregates contribute to the progressive loss of neurons and neurological symptoms.
Prion diseases, such as Creutzfeldt-Jakob disease, are a category where misfolded proteins can induce normal proteins to misfold in a chain reaction. The abnormal prion protein, PrPSc, acts as a template, converting normal cellular prion protein (PrPC) into the pathogenic form, leading to rapid neurodegeneration. Understanding protein misfolding mechanisms is a pathway to developing therapeutic strategies for these conditions.