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Sci Rep. 2016 Sep 16;6:33631. doi: 10.1038/srep33631.

The N-terminal domain plays a crucial role in the structure of a full-length human mitochondrial Lon protease.

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Institute of Cellular Biology and Pathology, First Faculty of Medicine, Charles University in Prague, Albertov 4, 128 01 Prague 2, Czech Republic.
Université de Grenoble Alpes,CNRS UMR 5309, 38042 Grenoble Cedex 9, France.
Department of Biochemistry and Structural Biology, Institute of Molecular Biology, Slovak Academy of Sciences, Bratislava, Slovakia.
Institute of Microbiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Biomedicine Center of the Academy of Sciences and Charles University in Vestec, Czech Republic.


Lon is an essential, multitasking AAA(+) protease regulating many cellular processes in species across all kingdoms of life. Altered expression levels of the human mitochondrial Lon protease (hLon) are linked to serious diseases including myopathies, paraplegia, and cancer. Here, we present the first 3D structure of full-length hLon using cryo-electron microscopy. hLon has a unique three-dimensional structure, in which the proteolytic and ATP-binding domains (AP-domain) form a hexameric chamber, while the N-terminal domain is arranged as a trimer of dimers. These two domains are linked by a narrow trimeric channel composed likely of coiled-coil helices. In the presence of AMP-PNP, the AP-domain has a closed-ring conformation and its N-terminal entry gate appears closed, but in ADP binding, it switches to a lock-washer conformation and its N-terminal gate opens, which is accompanied by a rearrangement of the N-terminal domain. We have also found that both the enzymatic activities and the 3D structure of a hLon mutant lacking the first 156 amino acids are severely disturbed, showing that hLon's N-terminal domains are crucial for the overall structure of the hLon, maintaining a conformation allowing its proper functioning.

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