9CC0

Human Mitochondrial LONP1 Degrading Casein, ATP-bound closed form

Summary for 9CC0

• Entry DOI: 10.2210/pdb9cc0/pdb
• EMDB information: 45430
• Descriptor: Lon protease homolog, mitochondrial, Bound substrate segment undergoing translocation and subsequent degradation, ADENOSINE-5'-TRIPHOSPHATE, ... (5 entities in total)
• Functional Keywords: atpase, protease, hydrolase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 7
• Total formula weight: 588828.56

Authors

Mindrebo, J.T.,Lander, G.C. (deposition date: 2024-06-20, release date: 2024-08-07)

Primary citation

Mindrebo, J.T.,Lander, G.C.
Structural and mechanistic studies on human LONP1 redefine the hand-over-hand translocation mechanism.
Biorxiv, 2024

PubMed Abstract: AAA+ enzymes use energy from ATP hydrolysis to remodel diverse cellular targets. Structures of substrate-bound AAA+ complexes suggest that these enzymes employ a conserved hand-over-hand mechanism to thread substrates through their central pore. However, the fundamental aspects of the mechanisms governing motor function and substrate processing within specific AAA+ families remain unresolved. We used cryo-electron microscopy to structurally interrogate reaction intermediates from in vitro biochemical assays to inform the underlying regulatory mechanisms of the human mitochondrial AAA+ protease, LONP1. Our results demonstrate that substrate binding allosterically regulates proteolytic activity, and that LONP1 can adopt a configuration conducive to substrate translocation even when the ATPases are bound to ADP. These results challenge the conventional understanding of the hand-over-hand translocation mechanism, giving rise to an alternative model that aligns more closely with biochemical and biophysical data on related enzymes like ClpX, ClpA, the 26S proteasome, and Lon protease.

PubMed: 38979310
DOI: 10.1101/2024.06.24.600538

Experimental method

ELECTRON MICROSCOPY (3.31 Å)