7KSL

Substrate-free human mitochondrial LONP1

7KSL の概要

• エントリーDOI: 10.2210/pdb7ksl/pdb
• EMDBエントリー: 23013 23019 23020
• 分子名称: Lon protease homolog, mitochondrial, ADENOSINE-5'-DIPHOSPHATE (2 entities in total)
• 機能のキーワード: aaa+, atpase, protease, mitochondrial, lonp1, lon, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 294626.49

構造登録者

Shin, M.,Watson, E.R.,Song, A.S.,Mindrebo, J.T.,Novick, S.R.,Griffin, P.,Wiseman, R.L.,Lander, G.C. (登録日: 2020-11-23, 公開日: 2020-12-09, 最終更新日: 2024-05-29)

主引用文献

Shin, M.,Watson, E.R.,Song, A.S.,Mindrebo, J.T.,Novick, S.J.,Griffin, P.R.,Wiseman, R.L.,Lander, G.C.
Structures of the human LONP1 protease reveal regulatory steps involved in protease activation.
Nat Commun, 12:3239-3239, 2021

PubMed Abstract: 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 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 underlying molecular mechanisms governing 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. Unlike bacterial Lon, human LONP1 contains a second spiral staircase within its ATPase domain that engages substrate as it is translocated toward the proteolytic chamber. Intriguingly, and in contrast to its bacterial ortholog, substrate binding within the central ATPase channel of LONP1 alone is insufficient to induce the activated conformation of the protease domains. To successfully induce the active protease conformation in substrate-bound LONP1, substrate binding within the protease active site is necessary, which we demonstrate by adding bortezomib, a peptidomimetic active site inhibitor of LONP1. These results suggest LONP1 can decouple ATPase and protease activities depending on whether AAA+ or both AAA+ and protease domains bind substrate. Importantly, our structures provide a molecular framework to define the critical importance of LONP1 in regulating mitochondrial proteostasis in health and disease.

PubMed: 34050165
DOI: 10.1038/s41467-021-23495-0

実験手法

ELECTRON MICROSCOPY (3.5 Å)