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Information on EC 3.4.24.B18 - m-AAA protease and Organism(s) Mus musculus and UniProt Accession Q3ULF4
for references in articles please use BRENDA:EC3.4.24.B18preliminary BRENDA-supplied EC number
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3.4.24.B18 m-AAA proteaseSpecify your search results
Word Map
- 3.4.24.B18
- paraplegia
- hereditary
- ataxia
- spinocerebellar
- atpases
- oma1
-
proteostasis
-
cristae
-
dynamin-like
-
homo-oligomeric
- paraparesis
- spastin
-
hetero-oligomeric
-
inner-membrane
- medicine
The taxonomic range for the selected organisms is: Mus musculus
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Synonyms
afg3l2, paraplegin, yme1l, m-aaa protease, afg3l1, aaa protease, yta10, yta12, yta12p, mitochondrial aaa protease, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
m-AAA protease
m-AAA protease comprises both heterooligomeric paraplegin-AFG3L2 and homo-oligomeric AFG3L2 isoenzymes
AFG3-like protein 2
AFG3L2
m-AAA protease
m-AAA protease
m-AAA protease comprises both heterooligomeric paraplegin-AFG3L2 and homo-oligomeric AFG3L2 isoenzymes
CAS REGISTRY NUMBER
COMMENTARY
213390-44-4
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
Oma1 + H2O
?
substrate is a zinc metallopeptidase of the inner mitochondrial membrane
-
-
?
protein OAP1 + H2O
?
-
homo-oligomeric m-AAA protease complexes composed of murine Afg3l1, Afg3l2, or human AFG3L2 subunits cleave OPA1 with higher efficiency than paraplegin-containing m-AAA proteases
-
-
?
MrpL32 + H2O
?
-
in vivo substrate, m-AAA does not affect the stability of the protein but cleaves the N-terminal mitochondrial targeting sequence upon protein import into the mitochondrion
-
-
?
additional information
?
-
strong genetic interaction between Afg3l2 and Spg7 in adult neurons, indicating that both m-AAA protease isoenzymes are required to prevent degenerative changes. The m-AAA protease protects against cerebellar degeneration. Spg72/2 mice show a late-onset degeneration of long spinal and peripheral axons with accumulation of abnormal mitochondria. m-AAA protease affects mt-DNA content and stability of the respiratory complexes
-
-
?
additional information
?
-
strong genetic interaction between Afg3l2 and Spg7 in adult neurons, indicating that both m-AAA protease isoenzymes are required to prevent degenerative changes. The m-AAA protease protects against cerebellar degeneration. Spg72/2 mice show a late-onset degeneration of long spinal and peripheral axons with accumulation of abnormal mitochondria. m-AAA protease affects mt-DNA content and stability of the respiratory complexes
-
-
?
additional information
?
-
strong genetic interaction between Afg3l2 and Spg7 in adult neurons, indicating that both m-AAA protease isoenzymes are required to prevent degenerative changes. The m-AAA protease protects against cerebellar degeneration. Spg72/2 mice show a late-onset degeneration of long spinal and peripheral axons with accumulation of abnormal mitochondria. m-AAA protease affects mt-DNA content and stability of the respiratory complexes
-
-
?
additional information
?
-
strong genetic interaction between Afg3l2 and Spg7 in adult neurons, indicating that both m-AAA protease isoenzymes are required to prevent degenerative changes. The m-AAA protease protects against cerebellar degeneration. Spg72/2 mice show a late-onset degeneration of long spinal and peripheral axons with accumulation of abnormal mitochondria. m-AAA protease affects mt-DNA content and stability of the respiratory complexes
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
MrpL32 + H2O
?
-
in vivo substrate, m-AAA does not affect the stability of the protein but cleaves the N-terminal mitochondrial targeting sequence upon protein import into the mitochondrion
-
-
?
additional information
?
-
strong genetic interaction between Afg3l2 and Spg7 in adult neurons, indicating that both m-AAA protease isoenzymes are required to prevent degenerative changes. The m-AAA protease protects against cerebellar degeneration. Spg72/2 mice show a late-onset degeneration of long spinal and peripheral axons with accumulation of abnormal mitochondria. m-AAA protease affects mt-DNA content and stability of the respiratory complexes
-
-
?
additional information
?
-
strong genetic interaction between Afg3l2 and Spg7 in adult neurons, indicating that both m-AAA protease isoenzymes are required to prevent degenerative changes. The m-AAA protease protects against cerebellar degeneration. Spg72/2 mice show a late-onset degeneration of long spinal and peripheral axons with accumulation of abnormal mitochondria. m-AAA protease affects mt-DNA content and stability of the respiratory complexes
-
-
?
additional information
?
-
strong genetic interaction between Afg3l2 and Spg7 in adult neurons, indicating that both m-AAA protease isoenzymes are required to prevent degenerative changes. The m-AAA protease protects against cerebellar degeneration. Spg72/2 mice show a late-onset degeneration of long spinal and peripheral axons with accumulation of abnormal mitochondria. m-AAA protease affects mt-DNA content and stability of the respiratory complexes
-
-
?
additional information
?
-
strong genetic interaction between Afg3l2 and Spg7 in adult neurons, indicating that both m-AAA protease isoenzymes are required to prevent degenerative changes. The m-AAA protease protects against cerebellar degeneration. Spg72/2 mice show a late-onset degeneration of long spinal and peripheral axons with accumulation of abnormal mitochondria. m-AAA protease affects mt-DNA content and stability of the respiratory complexes
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
abnormal dysfunctional mitochondria in Purkinje cells of Spg7-/- Afg3l2Emv66/+ mice
abnormal dysfunctional mitochondria in Purkinje cells of Spg7-/- Afg3l2Emv66/+ mice
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
-
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
physiological function
physiological function
-
mutations in the mitochondrial m-AAA protease genes cause two different neurodegenerative diseases in humans
physiological function
-
regulates OPA1 cleavage in mitochondrial inner membrane
physiological function
-
subunit AFG3L2 is required cell-autonomously for survival of adult neurons
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
-
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
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
-
hetero-oligomer variably formed by the Spg7 (paraplegin), Afg3l1, and Afg3l2 encoded proteins, or a homo-oligomer formed by either Afg3l1 or Afg3l2
additional information
-
subunits: paraplegin, AFG3L1 and AFG3L2; AFG3L1 forms homo-oligomeric complexes as well as hetero-oligomeric complexes with AFG3L2 and paraplegin; the mitochondrial processing peptidase MPP generates an intermediate form of AFG3L2 that is matured autocatalytically; AFG3L1 or AFG3L2 are also required for maturation of newly imported paraplegin subunits after their cleavage by MPP, mammalian m-AAA proteases can act as processing enzymes in vivo and reveal overlapping activities of AFG3L1 and AFG3L2
additional information
-
variable assembly of the subunits paraplegin, AFG3L1 and AFG3L2
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
-
deletion of subunit paraplegin, maturation of yeast MrpL32 protein is impaired. Functional conservation of yeast Yta10/Yta12 and murine paraplegin/Afg3L2
additional information
-
in a mutant form of AFG3L2, in which the aromatic residues within the caveolin-1-binding domain are substituted with alanines, the interaction with caveolin-1 is dramatically compromised
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Nolden, M.; Ehses, S.; Koppen, M.; Bernacchia, A.; Rugarli, E.I.; Langer, T.
The m-AAA protease defective in hereditary spastic paraplegia controls ribosome assembly in mitochondria
Cell
123
277-289
2005
Saccharomyces cerevisiae, Mus musculus
Duvezin-Caubet, S.; Koppen, M.; Wagener, J.; Zick, M.; Israel, L.; Bernacchia, A.; Jagasia, R.; Rugarli, E.I.; Imhof, A.; Neupert, W.; Langer, T.; Reichert, A.S.
OPA1 processing reconstituted in yeast depends on the subunit composition of the m-AAA protease in mitochondria
Mol. Biol. Cell
18
3582-3590
2007
Mus musculus
Koppen, M.; Metodiev, M.D.; Casari, G.; Rugarli, E.I.; Langer, T.
Variable and tissue-specific subunit composition of mitochondrial m-AAA protease complexes linked to hereditary spastic paraplegia
Mol. Cell. Biol.
27
758-767
2007
Mus musculus
Rugarli, E.I.; Langer, T.
Translating m-AAA protease function in mitochondria to hereditary spastic paraplegia
Trends Mol. Med.
12
262-269
2006
Saccharomyces cerevisiae, Homo sapiens, Mus musculus
Martinelli, P.; La Mattina, V.; Bernacchia, A.; Magnoni, R.; Cerri, F.; Cox, G.; Quattrini, A.; Casari, G.; Rugarli, E.I.
Genetic interaction between the m-AAA protease isoenzymes reveals novel roles in cerebellar degeneration
Hum. Mol. Genet.
18
2001-2013
2009
Homo sapiens (Q9UQ90), Homo sapiens (Q9Y4W6), Homo sapiens, Mus musculus (Q3ULF4), Mus musculus (Q8JZQ2)
Sacco, T.; Boda, E.; Hoxha, E.; Pizzo, R.; Cagnoli, C.; Brusco, A.; Tempia, F.
Mouse brain expression patterns of Spg7, Afg3l1, and Afg3l2 transcripts, encoding for the mitochondrial m-AAA protease
BMC Neurosci.
11
55
2010
Mus musculus
Ehses, S.; Raschke, I.; Mancuso, G.; Bernacchia, A.; Geimer, S.; Tondera, D.; Martinou, J.C.; Westermann, B.; Rugarli, E.I.; Langer, T.
Regulation of OPA1 processing and mitochondrial fusion by m-AAA protease isoenzymes and OMA1
J. Cell Biol.
187
1023-1036
2009
Homo sapiens (Q9Y4W6), Homo sapiens, Mus musculus
Koppen, M.; Bonn, F.; Ehses, S.; Langer, T.
Autocatalytic processing of m-AAA protease subunits in mitochondria
Mol. Biol. Cell
20
4216-4224
2009
Mus musculus
Kondadi, A.K.; Wang, S.; Montagner, S.; Kladt, N.; Korwitz, A.; Martinelli, P.; Herholz, D.; Baker, M.J.; Schauss, A.C.; Langer, T.; Rugarli, E.I.
Loss of the m-AAA protease subunit AFG3L2 causes mitochondrial transport defects and tau hyperphosphorylation
EMBO J.
33
1011-1026
2014
Mus musculus
Volonte, D.; Liu, Z.; Shiva, S.; Galbiati, F.
Caveolin-1 controls mitochondrial function through regulation of m-AAA mitochondrial protease
Aging
8
2355-2369
2016
Mus musculus
Murru, S.; Hess, S.; Barth, E.; Almajan, E.R.; Schatton, D.; Hermans, S.; Brodesser, S.; Langer, T.; Kloppenburg, P.; Rugarli, E.I.
Astrocyte-specific deletion of the mitochondrial m-AAA protease reveals glial contribution to neurodegeneration
Glia
67
1526-1541
2019
Mus musculus (Q920A7 and Q8JZQ2), Mus musculus
Consolato, F.; Maltecca, F.; Tulli, S.; Sambri, I.; Casari, G.
m-AAA and i-AAA complexes coordinate to regulate OMA1, the stress-activated supervisor of mitochondrial dynamics
J. Cell Sci.
131
jcs213546
2018
Mus musculus (Q8JZQ2)
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