Proteins are complex molecular machines performing nearly all functions within living organisms, from catalyzing reactions to transporting molecules and providing structural support. These molecules begin as linear chains of amino acids, but their ability to perform specific tasks depends on acquiring a precise three-dimensional shape. This process, known as protein folding, ensures each protein adopts its functional conformation.
How Proteins Achieve Their Shape
Proteins begin as a linear sequence of amino acids, their primary structure. This sequence guides the protein’s final form. These chains fold into localized patterns like alpha-helices (coiled springs) and beta-sheets (pleated structures). These local arrangements form the secondary structure, stabilized by hydrogen bonds within the polypeptide backbone.
Secondary structures then pack to form the overall three-dimensional shape of a single polypeptide chain, known as the tertiary structure. This architecture is stabilized by interactions between amino acid side chains, including hydrophobic interactions, hydrogen bonds, and ionic bonds. Hydrophobic amino acids often cluster in the protein’s core, away from water, while charged amino acids form salt bridges.
Some proteins consist of multiple polypeptide chains, or subunits. When these individual folded subunits combine, they form a larger, functional complex, termed the quaternary structure. These interactions are maintained by non-covalent forces such as electrostatic interactions, van der Waals forces, and hydrogen bonding. The amino acid sequence contains the information needed for a protein to achieve its native, functional state, often during its synthesis.
Cellular Helpers in Folding
While some proteins fold spontaneously, many require assistance from specialized cellular proteins called molecular chaperones. Chaperones are important in the crowded cellular environment, where misfolding and aggregation can occur. They bind to newly synthesized or partially folded proteins, preventing premature clumping or incorrect folding.
Chaperones guide folding by binding to exposed hydrophobic regions. Many are classified as heat shock proteins (HSPs) because their production increases in response to elevated temperatures or cellular stresses. Hsp70 and chaperonin (Hsp60) families use ATP-driven mechanisms to assist folding, providing a protected environment for polypeptides.
Even with chaperone assistance, some proteins misfold. Cells have quality control systems to deal with these aberrant proteins. The ubiquitin-proteasome system tags misfolded or damaged proteins with ubiquitin, marking them for degradation by the proteasome. This large protein complex breaks down unwanted proteins into smaller peptides, maintaining cellular health and preventing toxic aggregates.
When Folding Goes Wrong
When proteins fail to fold correctly, they can lose function or gain toxic properties. Misfolded proteins often become sticky and aggregate, forming insoluble clumps that disrupt cellular processes and are linked to various human diseases. These aggregates can lead to cellular stress, inflammation, and cell damage or death.
Neurodegenerative disorders are associated with protein misfolding and aggregation. Alzheimer’s disease involves amyloid-beta (Aβ) and tau protein accumulation in the brain, forming plaques and tangles that contribute to neuronal dysfunction and cognitive decline. Parkinson’s disease involves alpha-synuclein misfolding and aggregation, leading to Lewy body formation within brain cells, a hallmark contributing to motor and non-motor symptoms.
Huntington’s disease results from a genetic mutation causing an abnormally long polyglutamine tract in the huntingtin protein, making it prone to misfolding and aggregation. These mutant huntingtin aggregates interfere with cellular processes, leading to progressive neuron loss. Prion diseases, such as Creutzfeldt-Jakob disease, are caused by misfolded prion proteins (PrPSc) that can induce normal prion proteins (PrPC) to also misfold, leading to a cascade of aggregation and widespread brain damage.
What Influences Protein Folding
Protein folding is influenced by internal and external factors. Internally, changes to a protein’s primary amino acid sequence, often from genetic mutations, can impact its folding. Even “silent” mutations, which do not change the amino acid sequence, can affect how quickly a protein is synthesized, indirectly influencing correct folding.
External environmental stressors also disrupt protein folding. Extreme temperatures, for example, can cause proteins to unfold or “denature,” losing their three-dimensional structure. Changes in pH can alter amino acid side chain charge states, interfering with ionic and hydrogen bonds that stabilize protein shape. Oxidative stress, caused by an imbalance between free radicals and antioxidants, can also damage proteins and interfere with their folding. These insults can overwhelm the cell’s quality control mechanisms, leading to an increased burden of misfolded and aggregated proteins.