Disease-Associated Mutations in the HSPD1 Gene Encoding the Large Subunit of the Mitochondrial HSP60/HSP10 Chaperonin Complex.

Peter Bross,Paula Fernandez-Guerra

doi:10.3389/fmolb.2016.00049

Peter Bross, Paula Fernandez-Guerra

Open Access

https://doi.org/10.3389/fmolb.2016.00049

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Abstract

Heat shock protein 60 (HSP60) forms together with heat shock protein 10 (HSP10) double-barrel chaperonin complexes that are essential for folding to the native state of proteins in the mitochondrial matrix space. Two extremely rare monogenic disorders have been described that are caused by missense mutations in the HSPD1 gene that encodes the HSP60 subunit of the HSP60/HSP10 chaperonin complex. Investigations of the molecular mechanisms underlying these disorders have revealed that different degrees of reduced HSP60 function produce distinct neurological phenotypes. While mutations with deleterious or strong dominant negative effects are not compatible with life, HSPD1 gene variations found in the human population impair HSP60 function and depending on the mechanism and degree of HSP60 dys- and mal-function cause different phenotypes. We here summarize the knowledge on the effects of disturbances of the function of the HSP60/HSP10 chaperonin complex by disease-associated mutations.

Highlights

The type I chaperonins, a subclass of the molecular chaperone family of proteins, assist folding of proteins in the bacterial cytosol, the mitochondrial matrix space, and the chloroplast stroma
Cycles including binding of proteins undergoing folding to the Heat shock protein 60 (HSP60) rings, their encapsulation by association of heat shock protein 10 (HSP10) rings and dissociation of both the HSP10 ring and the enclosed protein are orchestrated by ATP binding, hydrolysis and release of ADP by the HSP60 subunits
Knock-out experiments have shown that the genes encoding homologs of the HSP60/HSP10 complex are essential in organisms from bacteria to mice (Cheng et al, 1989; Fayet et al, 1989; Perezgasga et al, 1999; Christensen et al, 2010)

Summary

INTRODUCTION

The type I chaperonins, a subclass of the molecular chaperone family of proteins, assist folding of proteins in the bacterial cytosol, the mitochondrial matrix space, and the chloroplast stroma. At present there are two amino acid variations in HSP60 known for which a clear diseaseassociation has been established: the HSP60-p.Val98Ile mutation associated with a dominantly inherited form of HSP (SPG13; OMIM #605280; Hansen et al, 2002) and the HSP60-p.Asp29Gly mutation causing a recessively inherited white matter disease called MitCHAP60 disease (OMIM #612233; Magen et al, 2008). Besides these two, a number of other variations have been described

ExAC allele count

Functional Analysis In vivo

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