Proteins are fundamental components of all living cells, performing diverse functions from catalyzing reactions to providing structural support. For a protein to carry out its specific role, it must achieve a precise three-dimensional shape, a process known as protein folding. However, proteins can sometimes misfold or fail to fold correctly, which can lead to dysfunction and aggregation within the cell. To address this challenge, cells possess remarkable molecular machinery that assists in the proper folding and maintenance of proteins. Among these, GroEL stands out as a sophisticated cellular machine that helps proteins acquire and sustain their correct folded structures.
Unveiling GroEL: The Cell’s Master Builder
GroEL is a chaperonin, a molecular chaperone that facilitates protein folding. Predominantly found in bacteria, GroEL is also a heat shock protein (Hsp60), with increased production under stress conditions like elevated temperatures. It frequently collaborates with a co-chaperonin called GroES, which acts as a cap for its structure. The GroEL complex is a large, cylindrical, barrel-shaped assembly.
The barrel consists of two stacked rings, each with seven identical protein subunits, forming a 14-subunit complex. Each GroEL subunit features three distinct sections: an apical domain that binds unfolded proteins and GroES, an intermediate domain, and an equatorial domain that binds ATP. Its interior initially provides a hydrophobic environment, crucial for interacting with unfolded or partially folded proteins that expose their hydrophobic regions. This creates a protective compartment for protein folding.
The GroEL Mechanism: A Molecular Assembly Line
GroEL assists in protein folding by providing an isolated chamber for refolding. The process begins when an unfolded or partially folded protein, exposing hydrophobic surfaces, binds to the hydrophobic patches within one of GroEL’s rings. Seven ATP molecules then associate with the same GroEL ring, initiating conformational changes. This ATP binding allows the co-chaperonin GroES to bind, acting as a lid to enclose the protein within the GroEL cavity.
Encapsulation transforms the GroEL chamber, making its hydrophobic lining hydrophilic. This encourages the enclosed protein to bury its hydrophobic residues internally, promoting correct folding. ATP hydrolysis to ADP within the complex provides energy for these changes. GroEL does not actively “fold” the protein; instead, it creates a protected, favorable environment, preventing aggregation. After about 10 seconds, ATP hydrolysis and subsequent ATP binding to the opposite GroEL ring release GroES and the folded protein from the chamber into the cellular environment.
GroEL’s Vital Role: Maintaining Cellular Harmony
GroEL maintains cellular protein homeostasis (proteostasis), balancing protein synthesis, folding, and degradation. It ensures 15-30% of cellular proteins achieve their correct functional structures. This is especially important under cellular stress, like heat shock, when proteins are prone to misfolding. During these periods, the cell increases GroEL production to counteract misfolded proteins.
Without GroEL, many newly synthesized or stress-denatured proteins would misfold and aggregate irreversibly. This accumulation disrupts essential cellular processes, leading to dysfunction and potential cell death. GroEL’s indispensable role in bacterial viability highlights its importance in cellular functioning and survival, especially during environmental challenges. This chaperonin system safeguards the cellular proteome’s functional integrity.
When GroEL Goes Awry: Implications for Health
As an essential protein for bacterial survival, GroEL has implications in bacterial pathogenesis. Its role in bacterial viability makes it a potential target for antimicrobial therapies. Beyond protein folding, GroEL exhibits “moonlighting functions” in some bacteria, performing activities unrelated to its chaperone role. For instance, bacterial GroEL is implicated in virulence, contributing to a bacterium’s ability to infect a host. It can be secreted and bind to host components, aiding adhesion or immune evasion.
In humans, Hsp60 is the mitochondrial homolog of GroEL. Hsp60 is vital for protein folding and transport within mitochondria, the cell’s powerhouses. Malfunctions of human Hsp60 link to mitochondrial disorders. Additionally, Hsp60 can act as an autoantigen, triggering an immune response against the body’s own tissues in some autoimmune conditions. While Hsp60 protects during stress, its extracellular presence or altered expression can contribute to inflammatory and autoimmune diseases, where the immune system attacks healthy cells.