Structures of the human LONP1 protease reveal regulatory steps involved in protease activation.
Structures of the human LONP1 protease reveal regulatory steps involved in protease activation.
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人类LONP1蛋白水解酶的结构揭示了参与酶激活的调控步骤。
DOI：
10.1038/s41467-021-23495-0
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发表时间：
2021-05-28
影响因子：
16.6
通讯作者：
Lander GC
中科院分区：
文献类型：
--
作者：
Shin M;Watson ER;Song AS;Mindrebo JT;Novick SJ;Griffin PR;Wiseman RL;Lander GC
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. The human mitochondrial protease LONP1 is an AAA+ ATP-dependent quality control protease. Here, the authors present the cryo-EM structures of human LONP1 in three distinct states and provide insights into the mechanism and regulation of this important protease.
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影响因子：
9
作者：
通讯作者：
--
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
56.9
作者：
Cooney, Ian;Han, Han;Shen, Peter S.
通讯作者：
Shen, Peter S.
影响因子：
10.5
作者：
Gur, Eyal;Sauer, Robert T.
通讯作者：
Sauer, Robert T.
ClpAP AAA+ 蛋白酶的构象可塑性与蛋白质解折叠和蛋白水解相结合。
影响因子：
16.8
作者：
Lopez KE;Rizo AN;Tse E;Lin J;Scull NW;Thwin AC;Lucius AL;Shorter J;Southworth DR
通讯作者：
Southworth DR