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Distinct Structural Features of the Lon Protease Drive Conserved Hand-over-Hand Substrate Translocation

By Mia Shin, Ananya Asmita, Cristina Puchades, Eric Adjei, R. Luke Wiseman, A. Wali Karzai, Gabriel C. Lander

Posted 24 Apr 2019
bioRxiv DOI: 10.1101/617159

Hand-over-hand translocation is emerging as the conserved mechanism by which ATP hydrolysis drives substrate translocation within the classical clade of AAA+ proteins. However, the operating principles of the distantly related HCLR clade, which includes the important quality control protease Lon, remains poorly defined. We determined a cryo-electron microscopy structure of Y. pestis Lon trapped in the act of processing substrate. This structure revealed that sequential ATP hydrolysis and hand-over-hand substrate translocation are conserved in this AAA+ protease. However, Lon processes substrates through a distinct molecular mechanism involving structural features unique to the HCLR clade. Our findings define a previously unobserved translocation mechanism that is likely conserved across HCLR proteins and reveal how fundamentally distinct structural configurations of distantly-related AAA+ enzymes can power hand-over-hand substrate translocation.

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