Activating Compound | Comment | Organism | Structure |
---|---|---|---|
DNA | Escherichia coli Lon binds both single stranded DNA (ssDNA) and RNA (ssRNA), and double stranded DNA (dsDNA) in a non-specific manner, and this interaction enhances Lon ATPase and proteolytic activities | Escherichia coli |
Crystallization (Comment) | Organism |
---|---|
crystal structure determination at 2.0 A resolution | Thermococcus onnurineus |
Protein Variants | Comment | Organism |
---|---|---|
S855A | the Lon mutant, which lacks both ATPase and proteolytic activity, still maintains DNA binding activity but, in this case, does not undergo conformational changes | Homo sapiens |
Localization | Comment | Organism | GeneOntology No. | Textmining |
---|---|---|---|---|
cell membrane | transmembrane enzyme | Thermococcus onnurineus | - |
- |
cytoplasm | - |
Escherichia coli | 5737 | - |
mitochondrion | - |
Homo sapiens | 5739 | - |
mitochondrion | - |
Mus musculus | 5739 | - |
mitochondrion | - |
Saccharomyces cerevisiae | 5739 | - |
Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
---|---|---|---|---|---|---|
5-aminolevulinic acid synthase + H2O | Homo sapiens | - |
? | - |
? | |
cystathionine beta-synthase + H2O | Homo sapiens | when misfolded or unfolded | ? | - |
? | |
cytochrome c oxidase 4 isoform 1 + H2O | Homo sapiens | i.e. COX4-1 | ? | - |
? | |
glutaminase C + H2O | Homo sapiens | when misfolded or unfolded | ? | - |
? | |
mitochondrial aconitase + H2O | Homo sapiens | when misfolded or unfolded | ? | - |
? | |
mitochondrial transcription factor A + H2O | Homo sapiens | i.e. TFAM | ? | - |
? | |
additional information | Escherichia coli | Escherichia coli Lon binds both single stranded DNA (ssDNA) and RNA (ssRNA), and double stranded DNA (dsDNA) in a non-specific manner, and this interaction enhances Lon ATPase and proteolytic activities | ? | - |
? | |
additional information | Saccharomyces cerevisiae | Lon binding partners are NADH dehydrogenase ubiquinone iron-sulfur protein 8 (NDUFS8), heat shock protein (Hsp)-60, and mtHsp70 | ? | - |
? | |
additional information | Saccharomyces cerevisiae ATCC 204508 | Lon binding partners are NADH dehydrogenase ubiquinone iron-sulfur protein 8 (NDUFS8), heat shock protein (Hsp)-60, and mtHsp70 | ? | - |
? | |
steroidogenic acute regulatory protein + H2O | Homo sapiens | - |
? | - |
? |
Organism | UniProt | Comment | Textmining |
---|---|---|---|
Escherichia coli | P0A9M0 | - |
- |
Homo sapiens | P36776 | - |
- |
Mus musculus | Q8CGK3 | - |
- |
Saccharomyces cerevisiae | P36775 | - |
- |
Saccharomyces cerevisiae ATCC 204508 | P36775 | - |
- |
Thermococcus onnurineus | B6YU74 | - |
- |
Posttranslational Modification | Comment | Organism |
---|---|---|
acetylation | human Lon is target of deacetylase sirtuin 3 (SIRT3), likely at Lys917, which is near the catalytic dyad, thus suggesting that Lon proteolytic activity can be regulated via deacetylation | Homo sapiens |
Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
---|---|---|---|---|---|---|
5-aminolevulinic acid synthase + H2O | - |
Homo sapiens | ? | - |
? | |
cystathionine beta-synthase + H2O | when misfolded or unfolded | Homo sapiens | ? | - |
? | |
cytochrome c oxidase 4 isoform 1 + H2O | i.e. COX4-1 | Homo sapiens | ? | - |
? | |
glutaminase C + H2O | when misfolded or unfolded | Homo sapiens | ? | - |
? | |
mitochondrial aconitase + H2O | when misfolded or unfolded | Homo sapiens | ? | - |
? | |
mitochondrial transcription factor A + H2O | i.e. TFAM | Homo sapiens | ? | - |
? | |
additional information | Escherichia coli Lon binds both single stranded DNA (ssDNA) and RNA (ssRNA), and double stranded DNA (dsDNA) in a non-specific manner, and this interaction enhances Lon ATPase and proteolytic activities | Escherichia coli | ? | - |
? | |
additional information | Lon binding partners are NADH dehydrogenase ubiquinone iron-sulfur protein 8 (NDUFS8), heat shock protein (Hsp)-60, and mtHsp70 | Saccharomyces cerevisiae | ? | - |
? | |
additional information | Lon efficiency in proteolysis can vary according to the status of its targets | Homo sapiens | ? | - |
? | |
additional information | Lon binding partners are NADH dehydrogenase ubiquinone iron-sulfur protein 8 (NDUFS8), heat shock protein (Hsp)-60, and mtHsp70 | Saccharomyces cerevisiae ATCC 204508 | ? | - |
? | |
steroidogenic acute regulatory protein + H2O | - |
Homo sapiens | ? | - |
? |
Subunits | Comment | Organism |
---|---|---|
hexamer | active enzyme form, modeling of the structure of the human mitochondrial Lon hexamer, overview | Homo sapiens |
More | while proteolytic activity is restricted at the P domain, chaperone activity is mediated by the ATP-binding domain and the N-terminal domain | Thermococcus onnurineus |
Synonyms | Comment | Organism |
---|---|---|
lon protease | - |
Homo sapiens |
lon protease | - |
Thermococcus onnurineus |
lon protease | - |
Escherichia coli |
lon protease | - |
Mus musculus |
lon protease | - |
Saccharomyces cerevisiae |
LONP1 | - |
Homo sapiens |
mitochondrial Lon protease | - |
Homo sapiens |
PIM1 | - |
Saccharomyces cerevisiae |
Protease La | - |
Escherichia coli |
TonLonB | - |
Thermococcus onnurineus |
Cofactor | Comment | Organism | Structure |
---|---|---|---|
ATP | dependent on | Homo sapiens | |
ATP | dependent on | Thermococcus onnurineus | |
ATP | dependent on | Escherichia coli | |
ATP | dependent on | Mus musculus | |
ATP | dependent on | Saccharomyces cerevisiae |
Organism | Comment | Expression |
---|---|---|
Homo sapiens | Lon is upregulated after serum starvation | up |
General Information | Comment | Organism |
---|---|---|
evolution | Lon proteases can be divided into two subfamilies: LonA (found in eubacteria and eukarya) and LonB (found in archaea). LonA proteases are formed by three functional domains: the N-terminal, involved in substrate binding, the central AAA+ domain, and the C-terminal domain (named P domain), which containing the Ser-Lys catalytic dyad for proteolytic activity. LonB proteases are composed by an ATPase and a protease domain and a hydrophobic transmembrane region which anchors the protein to the internal face of cell membrane | Thermococcus onnurineus |
evolution | Lon proteases can be divided into two subfamilies: LonA (found in eubacteria and eukarya) and LonB (found in archaea). LonA proteases are formed by three functional domains: the N-terminal, involved in substrate binding, the central AAA+ domain, and the C-terminal domain (named P domain), which containing the Ser-Lys catalytic dyad for proteolytic activity. LonB proteases are composed by an ATPase and a protease domain and a hydrophobic transmembrane region which anchors the protein to the internal face of cell membrane | Escherichia coli |
evolution | Lon proteases can be divided into two subfamilies: LonA (found in eubacteria and eukarya) and LonB (found in archaea). LonA proteases are formed by three functional domains: the N-terminal, involved in substrate binding, the central AAA+ domain, and the C-terminal domain (named P domain), which containing the Ser-Lys catalytic dyad for proteolytic activity. LonB proteases are composed by an ATPase and a protease domain and a hydrophobic transmembrane region which anchors the protein to the internal face of cell membrane. In eukarya, two Lon proteases are present: a mitochondrial and a peroxisomal form, encoded by two different genes | Homo sapiens |
evolution | Lon proteases can be divided into two subfamilies: LonA (found in eubacteria and eukarya) and LonB (found in archaea). LonA proteases are formed by three functional domains: the N-terminal, involved in substrate binding, the central AAA+ domain, and the C-terminal domain (named P domain), which containing the Ser-Lys catalytic dyad for proteolytic activity. LonB proteases are composed by an ATPase and a protease domain and a hydrophobic transmembrane region which anchors the protein to the internal face of cell membrane. In eukarya, two Lon proteases are present: a mitochondrial and a peroxisomal form, encoded by two different genes | Mus musculus |
evolution | Lon proteases can be divided into two subfamilies: LonA (found in eubacteria and eukarya) and LonB (found in archaea). LonA proteases are formed by three functional domains: the N-terminal, involved in substrate binding, the central AAA+ domain, and the C-terminal domain (named P domain), which containing the Ser-Lys catalytic dyad for proteolytic activity. LonB proteases are composed by an ATPase and a protease domain and a hydrophobic transmembrane region which anchors the protein to the internal face of cell membrane. In eukarya, two Lon proteases are present: a mitochondrial and a peroxisomal form, encoded by two different genes | Saccharomyces cerevisiae |
malfunction | downregulation leads to increased starvation-induced autophagy, and accumulation of PTEN-induced putative kinase-1 (PINK1), an essential regulator of mitophagy. Enzyme Lon is involved in genetic diseases and Lon protease plays a crucial role in the process of cell adaptation to a hypoxic environment, overview. Hypoxia leads to Lon upregulation in several cell types in humans, including monocytic acute myelogeneous leukaemia (THP-1), cardiomyocytes, embryonic kidney (293T) cells, rhabdomyosarcoma cells, renal cell carcinoma (RCC4) stably expressing Von Hippel-Lindau protein (VHL) | Homo sapiens |
malfunction | enzyme knockout is embryonically lethal in mice. Lon+/- mouse model, in which the expression of Lon is halved, is characterized by a lower tendency to develop cancer and a higher resistance to carcinogenic compounds than wild type counterparts. Accordingly, growth of Lon-silenced cancer cells in xenograft model is significantly reduced if compared to control cells, while cells overexpressing Lon grow more rapidly. In vivo, Lon overexpression favours glycolysis, facilitates proliferation, and capability to migrate and form metastasis of melanoma cells in nude mice | Mus musculus |
metabolism | functions of Lon protease in human mitochondria, overview. Lon expression highly correlates with expression of heat shock 60 kDa protein-1 (HSPD1), heat shock 10 kDa protein-1 (HSPE1), heat shock 70 kDa protein-9 (HSPA9), and caseinolytic mitochondrial matrix peptidase proteolytic subunit (CLPP), which are all involved in the mitochondrial unfolded protein response (UPRmt) | Homo sapiens |
additional information | the catalytic dyad required for peptide-bond hydrolysis is localized at Ser885-Lys896 | Homo sapiens |
additional information | the enzyme's active site has a Ser-Lys catalytic dyad | Escherichia coli |
additional information | while proteolytic activity is restricted at the P domain, chaperone activity ismediated by the ATP-binding domain and the N-terminal domain. The chaperone and degradation chambers are contiguous and there is virtually no constriction of the chamber between the chaperone domain and the protease active sites | Thermococcus onnurineus |
physiological function | Lon protease (Lonp1) is a nuclear encoded, mitochondrial ATP-dependent serine peptidase, which mediates the selective degradation of mutant and abnormal proteins in the organelle, and helps in the maintenance of mitochondrial homeostasis. Chaperone-like functions of Lon are involved in the assembly of mitochondrial membrane complexes in yeast and in humans, and, at least in yeast, these functions are maintained after inactivation of proteolytic site and are prevented when ATP-binding site is mutated. Together with its proteolytic and chaperone activities, Lon ability to bind DNA is conserved from bacteria to mammalian mitochondria. Lon ability to bind to DNA needs conformational changes in Lon itself, and such changes are inhibited by ATP, and are stimulated by a protein substrate | Saccharomyces cerevisiae |
physiological function | Lon protease (Lonp1) is a nuclear encoded, mitochondrial ATP-dependent serine peptidase, which mediates the selective degradation of mutant and abnormal proteins in the organelle, and helps in the maintenance of mitochondrial homeostasis. In humans, Lon is responsible for the degradation of: 1. stably folded proteins, including 5-aminolevulinic acid synthase, steroidogenic acute regulatory protein and mitochondrial transcription factor A (TFAM) and cytochrome c oxidase 4 isoform 1 (COX4-1), 2. misfolded and unfolded proteins, including glutaminase C, and 3. oxidatively-modified proteins, including mitochondrial aconitase and cystathionine beta-synthase. Lon proteolytic activity plays a role at different stages in the mitochondrial stress response. Chaperone-like functions of Lon are involved in the assembly of mitochondrial membrane complexes in yeast and in humans, and, at least in yeast, these functions are maintained after inactivation of proteolytic site and are prevented when ATP-binding site is mutated. Together with its proteolytic and chaperone activities, Lon ability to bind DNA is conserved from bacteria to mammalian mitochondria. Unlike bacterial Lon, human Lon binds specific ssDNA. Lon ability to bind to DNA needs conformational changes in Lon itself, and such changes are inhibited by ATP, and are stimulated by a protein substrate. By selectively degrading TFAM and controlling TFAM/mtDNA ratio, Lon is responsible for mitochondrial transcription maintenance. Role of Lon protease in carcinogenesis, overview | Homo sapiens |
physiological function | Lon protease (Lonp1) is a nuclear encoded, mitochondrial ATP-dependent serine peptidase, which mediates the selective degradation of mutant and abnormal proteins in the organelle, and helps in the maintenance of mitochondrial homeostasis. Together with its proteolytic and chaperone activities, Lon ability to bind DNA is conserved from bacteria to mammalian mitochondria. Lon ability to bind to DNA needs conformational changes in Lon itself, and such changes are inhibited by ATP, and are stimulated by a protein substrate | Mus musculus |
physiological function | together with its proteolytic and chaperone activities, Lon ability to bind DNA is conserved from bacteria to mammalian mitochondria. Lon ability to bind to DNA needs conformational changes in Lon itself, and such changes are inhibited by ATP, and are stimulated by a protein substrate | Thermococcus onnurineus |
physiological function | together with its proteolytic and chaperone activities, Lon ability to bind mtDNA is conserved from bacteria to mammalian mitochondria. Escherichia coli Lon binds both single stranded DNA (ssDNA) and RNA (ssRNA), and double stranded DNA (dsDNA) in a non-specific manner, and this interaction enhances Lon ATPase and proteolytic activities. Lon ability to bind to DNA needs conformational changes in Lon itself, and such changes are inhibited by ATP, and are stimulated by a protein substrate | Escherichia coli |