Hsp60 and Hsp70 Chaperones: Guardians of Mitochondrial Proteostasis

Abstract

Most protein molecules are dynamic and marginally stable and therefore constantly at risk for acquiring misfolded conformations. Constant surveillance is required to preserve proteostasis. Maintenance of the mitochondrial proteome relies on a diverse set of molecular chaperones and proteases, which together form an interconnected network. An imbalance in mitochondrial proteostasis will result in the accumulation of damaged polypeptides, potentially leading to collapse of mitochondrial integrity. The Hsp60 and Hsp70 chaperone systems play a central role in the folding of matrix‐localised proteins. In this article, we summarise major aspects of the molecular function of these nano‐machines and their interplay with other matrix chaperones and proteases.

Key Concepts

  • Hsp60 and Hsp70 chaperone systems play a crucial role in the maintenance of mitochondrial proteostasis.
  • Hsp60 and Hsp70 carry out various functions via interaction with a large number of extra‐mitochondrial complexes.
  • In addition to its critical role in protein import into the mitochondria, Hsp70 plays an important role in protein folding, disaggregation and degradation in the mitochondrial matrix.
  • Hsp60 is an essential protein that plays a central role in protein‐folding within the mitochondrial matrix.
  • The Hsp60 reaction cycle differs from that of GroEL in its incorporation of a single‐ring intermediate in the reaction cycle.

Keywords: mitochondrial proteostasis; Hsp60; Hsp70; protein folding; chaperones; disaggregation; protein import

Figure 1. Illustration of protein import and folding systems in yeast mitochondria. Every translocating protein enters the mitochondria as an unfolded precursor, through the TOM complex in the outer membrane. The inner‐membrane TIM23 complex recognises the precursor via the Tim50 subunit, which directs it through the membrane channel (Tim23 and Tim17). On the matrix side of the inner membrane, Hsp70 (Ssc1) works in concert with Tim44 and Mge1 to pull the precursor into the matrix. Folding in the matrix is generally carried out by Hsp60/10, disaggregation by Hsp78 and degradation by Pim1. Fe/S protein biosynthesis requires Ssq1, the scaffold protein Isu1 and its J‐type co‐chaperone Jac1. OM, outer membrane; IMS, inter membrane space; IM, inner membrane.
Figure 2. Mitochondrial Hsp70. (a) The Hsp70 reaction cycle. Interaction of Hsp70 with a J protein accelerates ADP hydrolysis and tight binding of substrate. NEF (nucleotide exchange factor) exchanges ADP (adenosine diphosphate) for ATP (adenosine triphosphate) and weakens binding of substrate. (b) Mitochondrial Hsp70 functions in three different capacities, in each one interacting with a different set of proteins: (1) with Mdj1 and Mge1 in mitochondrial protein folding; (2) with Tim44, Pam16, Pam18 and Mge1 in protein import; and (3) with Jac1, Mge1 and Isu1 in the assembly of iron–sulfur clusters.
Figure 3. The reaction cycle of mitochondrial Hsp60. On its own, Hsp60 exists as a single, 7‐membered ring to which denatured protein can bind. Subsequent binding of ATP and Hsp10 shifts the equilibrium to the double‐ringed form, which exhibits a ‘football’ structure. Hydrolysis of ATP to ADP eventually results in the release of the bound Hsp10, folded protein and ADP. Hsp60 subunits, Hsp10 subunits and substrate protein are coloured in magenta, blue and black, respectively.
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Further Reading

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Weiss C, Jebara F, Nisemblat S and Azem A (2016) Dynamic complexes in the chaperonin‐mediated protein folding cycle. Frontiers in Molecular Biosciences 3: 80.

Zuiderweg ERP, Hightower LE and Gestwicki JE (2017) The remarkable multivalency of the Hsp70 chaperones. Cell Stress & Chaperones 22: 173–189.

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Jebara, Fady, Weiss, Celeste, and Azem, Abdussalam(Sep 2017) Hsp60 and Hsp70 Chaperones: Guardians of Mitochondrial Proteostasis. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0027152]