Molecular chaperones involved in mitochondrial iron\u2013sulfur protein biogenesis

Rafal Dutkiewicz,Malgorzata Nowak

doi:10.1007/s00775-017-1504-x

Rafal Dutkiewicz, Malgorzata Nowak

Open Access

https://doi.org/10.1007/s00775-017-1504-x

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Abstract

Iron–sulfur (FeS) clusters are prosthetic groups critical for the function of many proteins in all domains of life. FeS proteins function in processes ranging from oxidative phosphorylation and cofactor biosyntheses to DNA/RNA metabolism and regulation of gene expression. In eukaryotic cells, mitochondria play a central role in the process of FeS biogenesis and support maturation of FeS proteins localized within mitochondria and in other cellular compartments. In humans, defects in mitochondrial FeS cluster biogenesis lead to numerous pathologies, which are often fatal. The generation of FeS clusters in mitochondria is a complex process. The [2Fe–2S] cluster is first assembled on a dedicated scaffold protein (Isu1) by the action of protein factors that interact with Isu1 to form the “assembly complex”. Next, the FeS cluster is transferred onto a recipient apo-protein. Genetic and biochemical evidence implicates participation of a specialized J-protein co-chaperone Jac1 and its mitochondrial (mt)Hsp70 chaperone partner, and the glutaredoxin Grx5 in the FeS cluster transfer process. Finally, various specialized ISC components assist in the generation of [4Fe–4S] clusters and cluster insertion into specific target apoproteins. Although a framework of protein components that are involved in the mitochondrial FeS cluster biogenesis has been established based on genetic and biochemical studies, detailed molecular mechanisms involved in this important and medically relevant process are not well understood. This review summarizes our molecular knowledge on chaperone proteins’ functions during the FeS protein biogenesis.

Highlights

Biogenesis of mitochondrial iron–sulfur (FeS) proteins requires the interaction of multiple proteins with the highly conserved 14-kDa scaffold protein Isu1, on which clusters are built prior to their transfer to recipient proteins
HscB/Jac1 interacts with Hsp70 via the N-terminal J-domain, which is highly similar to the J-domains of other J-proteins
We summarize the current knowledge on molecular chaperones which function in FeS protein biogenesis in mitochondria with an emphasis on the description of the molecular role and functional interactions with components of mitochondrial iron–sulfur cluster (ISC) assembly machinery

Summary

Introduction

Biogenesis of mitochondrial iron–sulfur (FeS) proteins requires the interaction of multiple proteins with the highly conserved 14-kDa scaffold protein Isu, on which clusters are built prior to their transfer to recipient proteins. In both the bacterial and mitochondrial systems, the C-terminal domain of Jac is directly responsible for Isu binding, with three hydrophobic residues playing a critical role in the interaction of Jac with Isu1 [51, 55, 57, 58] (Fig. 3) Substitution of these residues with alanine sharply reduces the interaction of Jac with Isu in vitro and severely compromises both cell growth and the activity of the FeS cluster containing enzymes in vivo. Reciprocal changes involving the sequence outside the loop region of Jac resulted in a highly specific and efficient interaction between Ssq and Jac, forming a chaperone machinery tuned for functioning exclusively in FeS cluster biogenesis. Lack of such competition could enable the increased rate of the Jac and Hsp sequence evolution

Functions of chaperones beyond the ATPase cycle

Future perspectives