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| Title | A 5+1 assemble-to-activate mechanism of the Lon proteolytic machine. |
|---|---|
| Journal, issue, pages | Nat Commun, Vol. 14, Issue 1, Page 7340, Year 2023 |
| Publish date | Nov 13, 2023 |
 Authors | Shanshan Li / Kan-Yen Hsieh / Chiao-I Kuo / Tzu-Chi Lin / Szu-Hui Lee / Yi-Ru Chen / Chun-Hsiung Wang / Meng-Ru Ho / See-Yeun Ting / Kaiming Zhang / Chung-I Chang /   |
| PubMed Abstract | Many AAA+ (ATPases associated with diverse cellular activities) proteins function as protein or DNA remodelers by threading the substrate through the central pore of their hexameric assemblies. In ...Many AAA+ (ATPases associated with diverse cellular activities) proteins function as protein or DNA remodelers by threading the substrate through the central pore of their hexameric assemblies. In this ATP-dependent translocating state, the substrate is gripped by the pore loops of the ATPase domains arranged in a universal right-handed spiral staircase organization. However, the process by which a AAA+ protein is activated to adopt this substrate-pore-loop arrangement remains unknown. We show here, using cryo-electron microscopy (cryo-EM), that the activation process of the Lon AAA+ protease may involve a pentameric assembly and a substrate-dependent incorporation of the sixth protomer to form the substrate-pore-loop contacts seen in the translocating state. Based on the structural results, we design truncated monomeric mutants that inhibit Lon activity by binding to the native pentamer and demonstrated that expressing these monomeric mutants in Escherichia coli cells containing functional Lon elicits specific phenotypes associated with lon deficiency, including the inhibition of persister cell formation. These findings uncover a substrate-dependent assembly process for the activation of a AAA+ protein and demonstrate a targeted approach to selectively inhibit its function within cells. |
 External links | Nat Commun / PubMed:37957149 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.4 - 5.8 Å |
| Structure data | EMDB-34000, PDB-7yph: EMDB-34001, PDB-7ypi: EMDB-34002, PDB-7ypj: EMDB-34003, PDB-7ypk:  EMDB-34004: Spiral hexamer of the substrate-free Lon protease with an S678A mutation  EMDB-34005: Open-spiral pentamer of the substrate-free Lon protease with Y397A and S678A mutations  EMDB-34006: Spiral hexamer of the substrate-free Lon protease with Y397A and S678A mutations EMDB-34107, PDB-7yuh: EMDB-34108, PDB-7yum: EMDB-34109, PDB-7yup: EMDB-34110, PDB-7yut: EMDB-34111, PDB-7yuu: EMDB-34112, PDB-7yuv: EMDB-34113, PDB-7yuw: EMDB-34114, PDB-7yux:  EMDB-34116: Spiral pentamer of the substrate-free Lon protease with an M217A mutation  EMDB-34117: Spiral hexamer of the substrate-free Lon protease with an M217A mutation  EMDB-36865: Spiral pentameric form of the substrate-free Lon protease with a Y224S mutation in the presence of the N-terminal-truncated monomeric mutant bearing an E613K mutation  EMDB-36866: Spiral hexameric form of the substrate-free Lon protease with a Y224S mutation in the presence of the N-terminal-truncated monomeric mutant bearing an E613K mutation EMDB-36867, PDB-8k3y: |
| Chemicals |  ChemComp-AGS:  ChemComp-ADP: |
| Source |
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 Keywords | HYDROLASE / Lon protease / hydrolysis / AAA proteins / AAA / protease / complex / proteolysis / Assembly / AAA+ protein / ATPase |
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