Regulation of mitochondrial protein import by the nucleotide exchange factors GrpEL1 and GrpEL2 in human cells

Srivastava, Shubhi and Savanur, Mohammad Azharuddin and Sinha, Devanjan and Birje, Abhijit and Vigneshwaran, R and Saha, Prasenjit Prasad and D'Silva, Patrick (2017) Regulation of mitochondrial protein import by the nucleotide exchange factors GrpEL1 and GrpEL2 in human cells. In: JOURNAL OF BIOLOGICAL CHEMISTRY, 292 (44). pp. 18075-18090.

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Abstract

Mitochondria are organelles indispensable for maintenance of cellular energy homeostasis. Most mitochondrial proteins are nuclearly encoded and are imported into the matrix compartment where they are properly folded. This process is facilitated by the mitochondrial heat shock protein 70 (mtHsp70), a chaperone contributing to mitochondrial protein quality control. The affinity of mtHsp70 for its protein clients and its chaperone function are regulated by binding of ATP/ADP to mtHsp70's nucleotide-binding domain. Nucleotide exchange factors (NEFs) play a crucial role in exchanging ADP for ATP at mtHsp70's nucleotide-binding domain, thereby modulating mtHsp70's chaperone activity. A single NEF, Mge1, regulates mtHsp70's chaperone activity in lower eukaryotes, but the mammalian orthologs are unknown. Here, we report that two putative NEF orthologs, GrpE-like 1 (GrpEL1) and GrpEL2, modulate mtHsp70's function in human cells. We found that both GrpEL1 and GrpEL2 associate with mtHsp70 as a hetero-oligomeric subcomplex and regulate mtHsp70 function. The formation of this subcomplex was critical for conferring stability to the NEFs, helped fine-tune mitochondrial protein quality control, and regulated crucial mtHsp70 functions, such as import of preproteins and biogenesis of Fe-S clusters. Our results also suggested that GrpEL2 has evolved as a possible stress resistance protein in higher vertebrates to maintain chaperone activity under stress conditions. In conclusion, our findings support the idea that GrpEL1 has a role as a stress modulator in mammalian cells and highlight that multiple NEFs are involved in controlling protein quality in mammalian mitochondria.

Item Type:	Journal Article
Publication:	JOURNAL OF BIOLOGICAL CHEMISTRY
Additional Information:	Copy right for this article belongs to the AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA
Department/Centre:	Division of Biological Sciences > Biochemistry
Date Deposited:	24 Nov 2017 10:14
Last Modified:	24 Nov 2017 10:14
URI:	http://eprints.iisc.ac.in/id/eprint/58300

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