Work

Structural basis for the allosteric activation of Lon by the heat shock protein LarA

Year: 2025

Type: article

Abstract: Lon is a conserved AAA+ (ATPases associated with diverse cellular activities) proteolytic machine that plays a key regulatory role in cells under proteotoxic stress. Lon-mediated proteolysis can be stimulated by either the unfolded or specific protein substrates accumulated under stress conditions. However, the molecular basis for this substrate-controlled proteolysis remains unclear. Here, we have found that the heat shock protein LarA, a recently discovered Lon substrate and allosteric activator, binds to the N-terminal domain (NTD) of Lon. The crystal structure of the LarA-NTD complex shows that LarA binds to a highly conserved groove in the NTD through the terminal aromatic residue of its C-terminal degron. Crystallographic and biochemical evidence further reveals that this binding exposes the hydrophobic core of LarA, which can bind a leucine residue and promote local protein unfolding. These results define the mechanistic role of the NTD in regulating Lon-mediated proteolysis in response to varying cellular conditions. Lon-mediated proteolysis can be stimulated by either the unfolded or specific protein substrates accumulated under stress conditions. Here, the authors unravel the mechanistic role of the N-terminal domain of Lon in this regulatory process.

Source: Nature Communications

DOI: 10.1038/s41467-025-57482-6

Authors: Hsiu-Jung Wang, Yun-Erh Kuan, Meng-Ru Ho, Chung-I Chang

Institutions: Institute of Biological Chemistry, Academia Sinica, Academia Sinica, National Taiwan University

Language: English

Topic: Heat shock proteins research

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: gold

Estimated APC paid: $6,990

Funder: Academia Sinica