Biochemical and biophysical research communicationsAug 11, 2024

Light-Triggered Binding of Hsc70 to a Specific Protein Tag in Cell Cleanup Processes in Mammal Cells

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 31, 2026

Abstract

The interaction between Hsc70 and the KFERQ-like pentapeptide motif was directly detected for the first time.

Hsc70 is a molecular chaperone that assists in protein folding and degradation.
It is involved in chaperone-mediated autophagy and endosomal microautophagy.
The study used a photo-crosslinker to confirm the direct binding of Hsc70 to the KFERQ motif.
A mutation that impairs Hsc70's ATPase activity significantly reduced the efficiency of this binding.
The findings indicate that ATP allostery plays a role in the interaction of Hsc70 with the KFERQ-like pentapeptide.

Simplified

Heat shock cognate protein 70 (Hsc70/HSPA8) belongs to the Hsp70 family of molecular chaperones. The fundamental functions of Hsp70 family molecular chaperones depend on ATP-dependent allosteric regulation of binding and release of hydrophobic polypeptide substrates. Hsc70 is also involved in various other cellular functions including selective pathways of protein degradation: chaperone-mediated autophagy (CMA) and endosomal microautophagy (eMI), in which Hsc70 recruits substrate proteins containing a KFERQ-like pentapeptide motif from the cytosol to lysosomes and late endosomes, respectively. However, whether the interaction between Hsc70 and the pentapeptide motif is direct or mediated by other molecules has remained unknown. In the present study, we introduced a photo-crosslinker near the KFERQ motif in a CMA/eMI model substrate and successfully detected its crosslinking with Hsc70, revealing the direct interaction between Hsc70 and the KFERQ motif for the first time. In addition, we demonstrated that the loss of the Hsc70 ATPase activity by the D10 N mutation appreciably reduced the crosslinking efficiency. Our present results suggested that the ATP allostery of Hsc70 is involved in the direct interaction of Hsc70 with the KFERQ-like pentapeptide.

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Competing interests

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Miki Hara-Yokoyama reports financial support was provided by LiberoThera Co., Ltd. Shigeyuki Yokoyama reports a relationship with LiberoThera Co., Ltd that includes: funding grants. Kazue Terasawa reports a relationship with LiberoThera Co., Ltd that includes: employment. There is no patents to disclose relevant to this work. has patent NA pending to NA. There is no additional relationships or activities to declare. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

PubMed

Light-Triggered Binding of Hsc70 to a Specific Protein Tag in Cell Cleanup Processes in Mammal Cells

Abstract

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Funding

Competing interests

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Abstract

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