Molecular machines known as chaperonins operate within all living cells. These specialized proteins play a fundamental role in ensuring that newly synthesized proteins, or those damaged by stress, achieve their correct three-dimensional shapes. Precise protein folding is necessary for them to carry out their specific tasks. Without the proper assistance provided by chaperonins, many proteins would misfold, leading to cellular dysfunction.
The Cell’s Protein Engineers
Chaperonins are a distinct class of proteins dedicated to assisting the proper folding of other proteins, often called client proteins. Proteins must adopt specific three-dimensional structures to perform their biological functions, such as catalyzing reactions or transporting molecules. If a protein fails to fold correctly, it can lose function or become harmful. Chaperonins act as molecular assistants, preventing misfolding and aggregation, which are common problems during protein synthesis or under cellular stress.
There are two major classes of chaperonins, categorized by evolutionary origin and cellular location. Group I chaperonins are found in prokaryotic organisms, like bacteria, and within the mitochondria and chloroplasts of eukaryotic cells. The bacterial GroEL/GroES system is a well-studied example. Group II chaperonins are present in the cytoplasm of eukaryotic cells and in archaea, with the TRiC/CCT complex being a prominent example in human cells.
How Chaperonins Work
Chaperonins facilitate protein folding by providing a secluded environment, often described as a “folding chamber,” where unfolded or partially folded proteins can achieve their correct structures without interference. This process begins when an unfolded protein enters the central cavity of the chaperonin complex. The chaperonin then encapsulates the protein, shielding it from the crowded cellular environment that could promote incorrect interactions or aggregation. This encapsulation step is driven by ATP binding.
Upon ATP hydrolysis, the chaperonin undergoes specific conformational changes that reshape the internal cavity and influence the client protein’s folding trajectory. This process helps gently unfold incorrectly formed regions within the client protein, allowing it to re-attempt folding. Once the protein achieves its correct three-dimensional conformation, the chaperonin complex releases it into the cellular environment. This ATP-dependent cycle ensures efficient and controlled protein maturation.
Chaperonins and Cellular Health
The proper functioning of chaperonins is directly linked to cellular health and survival. When proteins misfold, they expose hydrophobic regions normally hidden within the protein’s core, leading to inappropriate interactions with other proteins. This can result in insoluble protein aggregates, which are toxic clumps that disrupt cellular processes and can overwhelm the cell’s waste disposal systems. Chaperonins actively prevent the accumulation of these harmful aggregates by promoting correct folding or, if necessary, directing severely misfolded proteins for degradation.
Chaperonins are central to maintaining cellular proteostasis, a state of protein balance where protein synthesis, folding, and degradation are regulated. Their ability to manage protein quality control helps cells cope with various stresses, including heat shock, oxidative stress, and nutrient deprivation. By ensuring the cell’s protein machinery remains functional, chaperonins protect against cellular damage and contribute to cellular resilience. A breakdown in this system can lead to widespread cellular dysfunction and disease.
Chaperonins in Disease and Medicine
Dysfunction or altered expression of chaperonins is increasingly recognized for its involvement in various human diseases. In neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease, the accumulation of misfolded and aggregated proteins is a defining characteristic. Chaperonins are often found associated with these pathological protein deposits, suggesting their involvement in the cell’s attempt to clear or manage these toxic species. Their capacity to refold misfolded proteins makes them potential targets for therapeutic interventions aimed at preventing aggregate formation.
Chaperonins, particularly the Group II chaperonin TRiC/CCT, are also implicated in the progression of certain cancers. Cancer cells often exhibit increased protein synthesis and metabolic stress, making them more reliant on chaperonins for protein folding and survival. Overexpression of chaperonins in various tumors can support the rapid growth and proliferation of cancer cells by ensuring the folding of oncogenic proteins. This reliance makes chaperonins attractive targets for developing new anti-cancer drugs that disrupt their function, thereby selectively harming cancer cells.
Beyond neurodegeneration and cancer, chaperonins also play roles in infectious diseases. Some bacterial pathogens utilize their chaperonins to maintain virulence or adapt to host environments. Conversely, host chaperonins can interact with pathogen components, influencing the course of infection. Understanding these interactions opens avenues for developing novel antimicrobial strategies that target either the pathogen’s chaperonins or host-chaperonin interactions. Research continues to explore the therapeutic potential of modulating chaperonin activity.