The HSP60 chaperone protein is expressed in all tissues and it fulfils its essential role for cell survival within the mitochondria. The HSPD1 gene encodes the HSP60 protein, which is synthed in the cytosol with an N-terminal mitochondrial targeting sequence. The precursor protein is transported by the mitochondrial import system into the mitochondrial matrix space, where the targeting sequence is cleaved off. Mature HSP60 monomers fold and assemble to seven-membered ring structures with an inner cavity. The rings further assemble into back-to-back double rings. Folding proteins bind to the upper rim of the rings, enter the inner cavity, and are there encapsulated by a lid formed by seven-meric rings of the HSP10 protein encoded by the HSPE1 gene. Encapsulation, which allows proteins to fold undisturbed by other molecules. lasts for a few seconds. Then parallel ATP hydrolysis in all HSP60 subunits of one ring results in opening of the lid and release of the encapsulated protein.
The disease-associated mutations in the HSPD1 gene reported to date are all localized to a specific set of amino acid positions in a specific region of the structure in the equatorial domain of the protein, close to the ATP-binding site. Many mostly very rare and one polymorphic missense variations at amino acid positions distinct from those associated with disease have been registered in the Genome Aggregation Database (gnomAD; https://gnomad.broadinstitute.org/).
HSPD1