3.4.24.B18: m-AAA protease
This is an abbreviated version!
For detailed information about m-AAA protease, go to the full flat file.
Word Map on EC 3.4.24.B18
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3.4.24.B18
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paraplegia
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hereditary
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ataxia
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spinocerebellar
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atpases
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oma1
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proteostasis
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cristae
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dynamin-like
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homo-oligomeric
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paraparesis
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spastin
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hetero-oligomeric
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inner-membrane
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medicine
- 3.4.24.B18
- paraplegia
- hereditary
- ataxia
- spinocerebellar
- atpases
- oma1
-
proteostasis
-
cristae
-
dynamin-like
-
homo-oligomeric
- paraparesis
- spastin
-
hetero-oligomeric
-
inner-membrane
- medicine
Reaction
proteolytic degradation of proteins =
Synonyms
AAA protease, AFG3-like protein 2, Afg3l1, AFG3L2, ClpX, lon protease, m-AAA protease, m-AAA+ protease, M41.003, mitochondrial AAA protease, mitochondrial AAA+ protein, mitochondrial ATPase associated with various activities protease, mitochondrial mAAA protease, mitochondrial respiratory chain complexes assembly protein RCA1, paraplegin, SCRG_02514, SPG7, TAT-binding homolog 12, Yme1L, Yta10, Yta12, YTA12p
ECTree
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General Information
General Information on EC 3.4.24.B18 - m-AAA protease
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malfunction
metabolism
physiological function
malfunction
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enzyme knockdown in HeLa cells results in enlarged mitochondrial DNA nucleoids
malfunction
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enzyme knockdown stabilizes mitochondrial transcription factor A in mitochondrial DNA-deficient cells and upregulates mitochondrial DNA DNA
malfunction
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mutations in subunit AFG3L2 are associated with spinocerebellar ataxia SCA28. Depletion of subunit AFG3L2 leads to a specific defect of anterograde transport of mitochondria in cortical neurons. Deletion of subunit AFG3L2 in adult cortical neurons causes tau hyperphosphorylation and activation of protein kinase A and ERK1/2 kinases
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the m-AAA protease dislocates transmembrane segments from the mitochondrial inner membrane. The presence of the m-AAA protease increases the hydrophobicity required for a transmembrane segment to remain in the membrane. The m-AAA protease is a central component of the mitochondrial protein quality control system, being able to extract and degrade misfolded polypeptides from the inner membrane
metabolism
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the m-AAA protease dislocates transmembrane segments from the mitochondrial inner membrane. The presence of the m-AAA protease increases the hydrophobicity required for a transmembrane segment to remain in the membrane. The m-AAA protease is a central component of the mitochondrial protein quality control system, being able to extract and degrade misfolded polypeptides from the inner membrane
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mutations in the mitochondrial m-AAA protease genes cause two different neurodegenerative diseases in humans
physiological function
mutations in the SPG7 gene (paraplegin) cause an autosomal recessive form of hereditary spastic paraplegias
physiological function
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regulates OPA1 cleavage in mitochondrial inner membrane
physiological function
regulates OPA1 cleavage in mitochondrial inner membrane
physiological function
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MrpL32 ribosomal subunit processing is the central process controlled by the m-AAA protease in yeast
physiological function
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subunit AFG3L2 is required cell-autonomously for survival of adult neurons
physiological function
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the enzyme is a crucial component of the defense against accumulation of carbonylated proteins
physiological function
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the enzyme maintains mitochondrial DNA nucleoid distribution through mitochondrial transcription factor A function as a chaperone rather than as a protease and is involvement in mitochondrial DNA segregation
physiological function
Q920A7; Q8JZQ2
astrocyte-specific deletion of Afg3l2 in the mouse leads to late-onset motor impairment and to degeneration of Bergmann glia, which display aberrant morphology, altered expression of the glutamate transporter EAAT2, and a reactive inflammatory signature. The neurological and glial phenotypes are drastically exacerbated when astrocytes lack both subunits Afg31l and Afg3l2. Mitochondrial stress responses and necroptotic markers are induced in the cerebellum. In both mouse models, targeted Bergmann glia show a fragmented mitochondrial network and loss of mitochondrial cristae, but no signs of respiratory dysfunction. Astrocyte-specific deficiency of Afg3l1 and Afg3l2 triggers secondary morphological degeneration and electrophysiological changes in Purkinje cells
physiological function
both m-AAA and i-AAA complexes coordinately regulate OMA1 processing and turnover, and consequently control which OPA1 isoforms are present
physiological function
deletion of subunit AFG3L2 in mature mouse oligodendrocytes provokes early-on mitochondrial fragmentation and swelling. Total ablation of the m-AAA protease, by deleting both Afg3l2 and its paralogue Afg3l1, triggers progressive motor dysfunction and demyelination, owing to rapid oligodendrocyte cell death. The mice show premature hair greying, caused by progressive loss of melanoblasts
physiological function
in a mechanistic model, the ATP-bound subunits bind substrate, whereas the ADP-bound subunit releases the substrate at the lowest position of the spiral staircase, and the nucleotide-free subunit transitions to the highest position of the spiral staircase, where it reattaches to the substrate upon ATP-binding. The unfolded substrate is translocated in this fashion toward the negatively charged proteolytic chamber, where it is positioned for cleavage at the zinc-coordinated active site of the immutable planar protease domains
physiological function
Q9Y4W6; Q96TA2
loss of subunits AFG3L2 and YME1L, both alone and in combination, results in diminished cell proliferation, fragmentation of mitochondrial reticulum, altered cristae morphogenesis, and defective respiratory chain biogenesis. The double AFG3L2/YME1L knockdown cells show marked upregulation of dynamin-like protein OPA1 protein forms, with the most prominent increase in short OPA1 (optic atrophy 1). Loss of either protease leads to marked elevation in OMA1 zinc metallopeptidase and severe reduction in the SPG7 (paraplegin) subunit of the m-AAA complex. Loss of the YME1L subunit leads to an increased Drp1 level in mitochondrial fractions. Loss of YME1L impairs biogenesis and function of complex I, knockdown of AFG3L2 mainly affects the assembly and function of complex IV
physiological function
loss of the SPG7 gene increased resistance to Ca2+-induced mitochondrial permeability transition pore opening. This occurs independently of cyclophilin D (cyclosporine A insensitive) but rather it is through decreased mitochondrial Ca2+ concentrations and subsequent adaptations mediated by impaired formation of functional mitochondrial Ca2+ uniporter complexes. SPG7 directs the m-AAA complex to favor association with the mitochondrial Ca2+ uniporter, and mitochondrial Ca2+ uniporter processing regulates higher order mitochondrial Ca2+ uniporter-complex formation
physiological function
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protease AFG3L2 is a caveolin-1-interacting protein in vitro. Oxidative stress promotes the translocation of both caveolin-1 and AFG3L2 to mitochondria, enhances the interaction of caveolin-1 with AFG3L2 in mitochondria and stimulates mitochondrial protease activity in wild-type fibroblasts. Localization of AFG3L2 to mitochondria after oxidative stress is inhibited in fibroblasts lacking caveolin-1, which results in impaired mitochondrial protein quality control, an oxidative phosphorylation to aerobic glycolysis switch and reduced ATP production. Expression of a mutant form of AFG3L2 with reduced affinity for caveolin-1, fails to localize to mitochondria and promotes degradation of complex IV after oxidative stress
physiological function
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replacement of the subunit Yta10 TM2 domain abolishes membrane dislocation for only a subset of substrates, whereas replacement of the subunit Yta12 TM2 domain impairs membrane dislocation for all substrates tested. m-AAA protease-mediated membrane dislocation is impaired in the presence of a large downstream hydrophilic moiety in a membrane substrate
physiological function
SPG7 mutants exhibit shortened lifespan, progressive locomotor defects, sensitivity to chemical and environmental stress, and muscular and neuronal degeneration. The neurodegenerative phenotype of SPG7 mutants initiates at the synaptic terminal. A variety of mitochondrial defects are observed in the mutants, including altered axonal transport of mitochondria, accumulation of electron-dense material in the matrix of flight muscle mitochondria, reduced activities of respiratory chain complexes I and II, and severely swollen and dysmorphic mitochondria in the synaptic terminals of photoreceptors
physiological function
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in a mechanistic model, the ATP-bound subunits bind substrate, whereas the ADP-bound subunit releases the substrate at the lowest position of the spiral staircase, and the nucleotide-free subunit transitions to the highest position of the spiral staircase, where it reattaches to the substrate upon ATP-binding. The unfolded substrate is translocated in this fashion toward the negatively charged proteolytic chamber, where it is positioned for cleavage at the zinc-coordinated active site of the immutable planar protease domains
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physiological function
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replacement of the subunit Yta10 TM2 domain abolishes membrane dislocation for only a subset of substrates, whereas replacement of the subunit Yta12 TM2 domain impairs membrane dislocation for all substrates tested. m-AAA protease-mediated membrane dislocation is impaired in the presence of a large downstream hydrophilic moiety in a membrane substrate
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