Rxivist logo

Structures of the Human LONP1 Protease Reveal Regulatory Steps Involved in Protease Activation

By Mia Shin, Edmond R. Watson, Scott J Novick, Patrick R Griffin, Luke Wiseman, Gabriel C. Lander

Posted 23 Nov 2020
bioRxiv DOI: 10.1101/2020.11.23.394858

The human mitochondrial AAA+ protein LONP1 is a critical quality control protease involved in regulating diverse aspects of mitochondrial biology including proteostasis, electron transport chain activity, and mitochondrial transcription. As such, genetic or aging-associated imbalances in LONP1 activity are implicated in the pathologic mitochondrial dysfunction associated with numerous human diseases. Despite this importance, the molecular basis for LONP1-dependent proteolytic activity remains poorly defined. Here, we solved cryo-electron microscopy structures of human LONP1 to reveal the molecular mechanism of substrate proteolysis. We show that, like bacterial Lon, human LONP1 adopts both an open and closed spiral staircase orientation dictated by the presence of substrate and nucleotide. However, unlike bacterial Lon, human LONP1 contains a second spiral staircase within its ATPase domain that engages substrate to increase interactions with the translocating peptide as it transits into the proteolytic chamber for proteolysis. Further, we show that substrate-bound LONP1 includes a second level of regulation at the proteolytic active site, wherein autoinhibition of the active site is only relieved by the presence of a peptide substrate. Ultimately, our results define a structural basis for human LONP1 proteolytic activation and activity, establishing a molecular framework to understand the critical importance of this protease for mitochondrial regulation in health and disease.

Download data

  • Downloaded 1,087 times
  • Download rankings, all-time:
    • Site-wide: 30,101
    • In molecular biology: 786
  • Year to date:
    • Site-wide: 62,070
  • Since beginning of last month:
    • Site-wide: 74,979

Altmetric data


Downloads over time

Distribution of downloads per paper, site-wide


PanLingua

News