GroEL is a protein which belongs to the chaperonin family of molecular chaperones, and is found in many bacteria. It is required for the proper folding of many proteins. To function properly, GroEL requires the lid-like cochaperonin protein complex GroES. In eukaryotes the organellar proteins Hsp60 and Hsp10 are structurally and functionally nearly identical to GroEL and GroES, respectively, due to their endosymbiotic origin. HSP60 is implicated in mitochondrial protein import and macromolecular assembly. It may facilitate the correct folding of imported proteins, and may also prevent misfolding and promote the refolding and proper assembly of unfolded polypeptides generated under stress conditions in the mitochondrial matrix. HSP60 interacts with HRAS and with HBV protein X and HTLV-1 protein p40tax. HSP60 belongs to the chaperonin (HSP60) family. Note: This description may include information from UniProtKB. Alternate Names: 60 kDa chaperonin, Chaperonin 60, CPN60, Heat shock protein 60, HSP-60, HuCHA60, Mitochondrial matrix protein P1, P60 lymphocyte protein, HSPD1 Heat shock protein 60 (HSP60) is a mitochondrial chaperonin that is typically held responsible for the transportation and refolding of proteins from the cytoplasm into the mitochondrial matrix. In addition to its role as a heat shock protein, HSP60 functions as a chaperonin to assist in folding linear amino acid chains into their respective three-dimensional structure. Through the extensive study of groEL, HSP60’s bacterial homolog, HSP60 has been deemed essential in the synthesis and transportation of essential mitochondrial proteins from the cell's cytoplasm into the mitochondrial matrix. Further studies have linked HSP60 to diabetes, stress response, cancer and certain types of immunological disorders.
Discovery Mammalian HSP60 was first reported as a mitochondrial P1 protein. It was subsequently cloned and sequenced by Radhey Gupta and coworkers. The amino acid sequence showed a strong homology to GroEL. It was initially believed that HSP60 functioned only in the mitochondria and that there was no equivalent protein located in the cytoplasm. Recent discoveries have discredited this claim and have suggested that there is a recognizable difference between HSP60 in the mitochondria and in the cytoplasm. A similar protein structure exists in the chloroplast of certain plants. This protein presence provides evidence for the evolutionary relationship of the development of the mitochondria and the chloroplast by means of endosymbiosis.
Structure Under normal physiological conditions, HSP60 is a 60 kilodalton oligomer composed of monomers that form a complex arranged as two stacked heptameric rings. This double ring structure forms a large central cavity in which the unfolded protein binds via hydrophobic interactions. This structure is typically in equilibrium with each of its individual components: monomers, heptamers, and tetradecamers. Recent studies have begun to suggest that in addition to its typical location in the mitochondria, HSP60 can also be found in the cytoplasm under normal physiological conditions. Each subunit of HSP60 has three domains: the apical domain, the equatorial domain, and the intermediate domain. The equatorial domain contains the binding site for ATP and for the other heptameric ring. The intermediate domain binds the equatorial domain and the apical domain together. The intermediate domain induces a conformational change when ATP is bound allowing for an alternation between the hydrophilic and hydrophobic substrate binding sites. In its inactive state, the protein is in a hydrophobic state. When activated by ATP, the intermediate domain undergoes a conformational change that exposes the hydrophilic region. This insures fidelity in protein binding. Chaperonin 10 aids HSP60 in folding by acting as a dome-like cover on the ATP active form of HSP60. This causes the central cavity to enlarge and aids in protein folding. See the above figure for further detail on the structure.
The mitochondrial HSP60 sequence contains a series of G repeats at the C-terminal. The structure and function of this sequence is not quite known. The N-terminal contains a pre-sequence of hydroxylated amino acids, namely arginine, lysine, serine, and threonine, which serve as directors for the importation of the protein into the mitochondria. The predicted structure of HSP60 includes several vertical sine waves, alpha helices, beta sheets, and 90 degree turns. There are regions of hydrophobicity where the protein presumably spans the membrane. There are also three N-linked glycosylation sites at positions 104, 230, 436. The sequence and secondary structure for the mitochondrial protein are illustrated in the above image obtained from the Protein Data Bank. Newer information has begun to suggest that the HSP60 found in the mitochondria differs from that of the cytoplasm. With respect to the amino acid sequence, the cytoplasmic HSP60 has an N-terminal sequence not found in the mitochondrial protein. In gel electrophoresis analysis, significant differences were found in the migration of cytoplasmic and mitochondrial HSP60. The cytoplasmic HSP60 contains a signal sequence of 26 amino acids on the N terminus. This sequence is highly degenerate and is capable of folding into amphiphilic helix. Antibodies against HSP60 targeted both the mitochondrial and cytoplasmic form. Nonetheless, antibodies against the signal sequence targeted only the cytoplasmic form. Under normal physiological condition, both are found in relatively equal concentrations. In times of stress or high need of HSP60 in either the cytoplasm or the mitochondria, the cell is capable for compensating by increasing the presence of HSP60 in one compartment and decreasing its concentration in the opposite compartment.
Function
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