Nucleotide exchange factors Fes1 and HspBP1 mimic substrate to release misfolded proteins from Hsp70

• Published in: Nature structural & molecular biology Vol. 25; no. 1; pp. 83 - 89
• Main Authors: Gowda, Naveen K. C., Kaimal, Jayasankar M., Kityk, Roman, Daniel, Chammiran, Liebau, Jobst, Öhman, Marie, Mayer, Matthias P., Andréasson, Claes
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 2018; Nature Publishing Group
• Subjects: 631/45/470/1981; 631/80/470/1981; Adaptor Proteins, Signal Transducing - chemistry; Adenosine Triphosphate - chemistry; Binding; Biochemistry; Biodegradation; Biological Microscopy; Biomedical and Life Sciences; Cells (Biology); Chaperones; DNA-Binding Proteins - metabolism; Domains; Exchanging; Genetic aspects; GTPases; Guanine Nucleotide Exchange Factors - metabolism; Heat shock proteins; Homology; HSP70 Heat-Shock Proteins - metabolism; Hsp70 protein; Humans; Intracellular Signaling Peptides and Proteins - chemistry; Life Sciences; Mammalian cells; Membrane Biology; Mimicry; Molecular chaperones; Molecular Chaperones - metabolism; Nucleotides; Nucleotides - metabolism; Peptides; Phenotype; Physiological aspects; Protein Denaturation; Protein Folding; Protein Structure; Proteins; Quality control; Respiratory distress syndrome; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - chemistry; Sjogren's syndrome; Specialization; Substrates; Transcription Factors - metabolism; Yeast; Yeasts; Sweden
• ISSN: 1545-9993; 1545-9985; 1545-9985
• DOI: 10.1038/s41594-017-0008-2

Protein quality control depends on the tight regulation of interactions between molecular chaperones and polypeptide substrates. Substrate release from the chaperone Hsp70 is triggered by nucleotide-exchange factors (NEFs) that control folding and degradation fates via poorly understood mechanisms. We found that the armadillo-type NEFs budding yeast Fes1 and its human homolog HspBP1 employ flexible N-terminal release domains (RDs) with substrate-mimicking properties to ensure the efficient release of persistent substrates from Hsp70. The RD contacts the substrate-binding domain of the chaperone, competes with peptide substrate for binding and is essential for proper function in yeast and mammalian cells. Thus, the armadillo domain engages Hsp70 to trigger nucleotide exchange, whereas the RD safeguards the release of substrates. Our findings provide fundamental mechanistic insight into the functional specialization of Hsp70 NEFs and have implications for the understanding of proteostasis-related disorders, including Marinesco–Sjögren syndrome. Nucleotide exchange factors (NEFs) trigger substrate release from molecular chaperone Hsp70. The authors found that armadillo-type NEFs (yeast Fes1, human HspBP1) competitively prevent rebinding of released substrate.