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Title | Structural and mechanistic studies on human LONP1 redefine the hand-over-hand translocation mechanism. |
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Journal, issue, pages | bioRxiv, Year 2024 |
Publish date | Jun 25, 2024 |
![]() | Jeffrey T Mindrebo / Gabriel C Lander / ![]() |
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 ...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. |
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Methods | EM (single particle) |
Resolution | 3.18 - 3.31 Å |
Structure data | EMDB-45430, PDB-9cc0: EMDB-45433, PDB-9cc3: ![]() EMDB-45434: LONP1 stall state bound to substrate and 4 ADPs |
Chemicals | ![]() ChemComp-ATP: ![]() ChemComp-MG: ![]() ChemComp-ADP: |
Source |
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![]() | HYDROLASE / ATPase / protease |