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Information on EC 3.4.24.B18 - m-AAA protease and Organism(s) Homo sapiens and UniProt Accession Q9UQ90
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: Homo sapiens
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
AFG3-like protein 2
AFG3L2
m-AAA protease
m-AAA protease
m-AAA protease comprises both heterooligomeric paraplegin-AFG3L2 and homo-oligomeric AFG3L2 isoenzymes
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
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. Loss of function of paraplegin (encoded by the SPG7 gene) causes hereditary spastic paraplegia, a disease characterized by retrograde degeneration of cortical motor axons
-
-
?
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. Loss of function of paraplegin (encoded by the SPG7 gene) causes hereditary spastic paraplegia, a disease characterized by retrograde degeneration of cortical motor axons
-
-
?
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. Loss of function of paraplegin (encoded by the SPG7 gene) causes hereditary spastic paraplegia, a disease characterized by retrograde degeneration of cortical motor axons
-
-
?
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
-
-
?
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
-
-
?
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
-
-
?
additional information
?
-
-
DNA-bound mitochondrial transcription factor A is resistant to proteolysis
-
-
?
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. Loss of function of paraplegin (encoded by the SPG7 gene) causes hereditary spastic paraplegia, a disease characterized by retrograde degeneration of cortical motor axons
-
-
?
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. Loss of function of paraplegin (encoded by the SPG7 gene) causes hereditary spastic paraplegia, a disease characterized by retrograde degeneration of cortical motor axons
-
-
?
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. Loss of function of paraplegin (encoded by the SPG7 gene) causes hereditary spastic paraplegia, a disease characterized by retrograde degeneration of cortical motor axons
-
-
?
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
-
-
?
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
-
-
?
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
-
-
?
additional information
?
-
-
DNA-bound mitochondrial transcription factor A is resistant to proteolysis
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
human mitochondria possess two m-AAA protease isoenzymes: a hetero-oligomeric complex, composed of paraplegin and AFG3L2 (Afg3 like 2), and a homo-oligomeric AFG3L2 complex. Genetic interaction between the m-AAA isoenzymes and suggest that different neuronal populations have variable thresholds of susceptibility to reduced levels of the m-AAA protease
the catalytic domain is located in the mitochondrial matrix
human mitochondria possess two m-AAA protease isoenzymes: a hetero-oligomeric complex, composed of paraplegin and AFG3L2 (Afg3 like 2), and a homo-oligomeric AFG3L2 complex. Genetic interaction between the m-AAA isoenzymes and suggest that different neuronal populations have variable thresholds of susceptibility to reduced levels of the m-AAA protease
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
mutations in the SPG7 gene (paraplegin) cause an autosomal recessive form of hereditary spastic paraplegias
malfunction
physiological function
malfunction
-
enzyme knockdown in HeLa cells results in enlarged mitochondrial DNA nucleoids
malfunction
-
enzyme knockdown stabilizes mitochondrial transcription factor A in mitochondrial DNA-deficient cells and upregulates mitochondrial DNA DNA
physiological function
regulates OPA1 cleavage in mitochondrial inner membrane
physiological function
-
the enzyme is a crucial component of the defense against accumulation of carbonylated proteins
physiological function
-
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
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
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
homohexamer
paraplegin (SPG7) subunit, crystal structure and homology with FtsH
additional information
additional information
hetero-oligomeric, paraplegin (encoded by SPG7 gene) and AFG3L2 subunits assembles into an oligomeric complex
additional information
-
hetero-oligomeric, paraplegin (encoded by SPG7 gene) and AFG3L2 subunits assembles into an oligomeric complex
additional information
variable assembly of the subunits subunits AFG3L2 and paraplegin
additional information
-
variable assembly of the subunits subunits AFG3L2 and paraplegin
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
AAA-domain of paraplegin bound to ADP, vapor diffusion method in sitting drops
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
A510V
subunit paraplegin, function impaired, naturally occuring pathogenic mutation
G349S
subunit paraplegin, function impaired, naturally occuring pathogenic mutation
W583C
subunit paraplegin, function impaired, naturally occuring pathogenic mutation
E359A
-
the mutant lacks ATPase activity but retains casein lytic protease activity
E408Q
subunit AFG3L2, within Walker B motif, cells expressing AFG3L2 (E408Q) show a prominent reduction of their growth rate
F381A
substitution abolishes substrate degradation, while only mildly impacting ATP hydrolysis
M683A
mutation moderately reduces substrate degradation while minimally affecting ATP hydrolysis
N432T
disease-relevant mutation, localizes to the vicinity of the nucleotide-binding pocket at the ATPase intersubunit interface
R468C
disease-relevant mutation, localizes to the vicinity of the nucleotide-binding pocket at the ATPase intersubunit interface
additional information
additional information
deleting the ordered, substrate-interacting ATPase N terminus (residues 272-295) significantly impaires substrate degradation. Truncation of the C-terminus at residue 750, decreases recovery ofAFG3L2 hexamers
additional information
-
deleting the ordered, substrate-interacting ATPase N terminus (residues 272-295) significantly impaires substrate degradation. Truncation of the C-terminus at residue 750, decreases recovery ofAFG3L2 hexamers
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
all of the autosomal dominant mutations, such as N432T and R468C, localize to intersubunit interfaces of the hexamer, including the lateral interface between adjacent ATPase subunits where the nucleotide binding pocket is formed, the tightly interconnected helices that dominate the lateral interface of the protease domain, and the central protrusion of the AFG3L2 protease ring that is involved in substrate transfer to the protease domains
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
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)
Bonn, F.; Pantakani, K.; Shoukier, M.; Langer, T.; Mannan, A.U.
Functional evaluation of paraplegin mutations by a yeast complementation assay
Hum. Mutat.
31
617-621
2010
Homo sapiens (Q9UQ90), Homo sapiens
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
Karlberg, T.; van den Berg, S.; Hammarstroem, M.; Sagemark, J.; Johansson, I.; Holmberg-Schiavone, L.; Schueler, H.
Crystal structure of the ATPase domain of the human AAA+ protein paraplegin/SPG7
PLoS ONE
4
e6975
2009
Homo sapiens (Q9UQ90), Homo sapiens
Smakowska, E.; Czarna, M.; Janska, H.
Mitochondrial ATP-dependent proteases in protection against accumulation of carbonylated proteins
Mitochondrion
19
245-251
2014
Homo sapiens
Kasashima, K.; Sumitani, M.; Endo, H.
Maintenance of mitochondrial genome distribution by mitochondrial AAA+ protein ClpX
Exp. Cell Res.
318
2335-2343
2012
Homo sapiens
Ramelot, T.A.; Yang, Y.; Sahu, I.D.; Lee, H.W.; Xiao, R.; Lorigan, G.A.; Montelione, G.T.; Kennedy, M.A.
NMR structure and MD simulations of the AAA protease intermembrane space domain indicates peripheral membrane localization within the hexaoligomer
FEBS Lett.
587
3522-3528
2013
Homo sapiens, Homo sapiens (Q9Y4W6)
Lowth, B.; Kirstein-Miles, J.; Saiyed, T.; Brtz-Oesterhelt, H.; Morimoto, R.; Truscott, K.; Dougan, D.
Substrate recognition and processing by a Walker B mutant of the human mitochondrial AAA+ protein CLPX
J. Struct. Biol.
179
193-201
2012
Homo sapiens
Lu, B.; Lee, J.; Nie, X.; Li, M.; Morozov, Y.I.; Venkatesh, S.; Bogenhagen, D.F.; Temiakov, D.; Suzuki, C.K.
Phosphorylation of human TFAM in mitochondria impairs DNA binding and promotes degradation by the AAA+ Lon protease
Mol. Cell
49
121-132
2013
Homo sapiens
Cesnekova, J.; Rodinova, M.; Hansikova, H.; Zeman, J.; Stiburek, L.
Loss of mitochondrial AAA proteases AFG3L2 and YME1L impairs mitochondrial structure and respiratory chain biogenesis
Int. J. Mol. Sci.
19
e9288
2018
Homo sapiens (Q9Y4W6 and Q96TA2)
Hurst, S.; Baggett, A.; Csordas, G.; Sheu, S.S.
SPG7 targets the m-AAA protease complex to process MCU for uniporter assembly, Ca2+ influx, and regulation of mitochondrial permeability transition pore opening
J. Biol. Chem.
294
10807-10818
2019
Homo sapiens (Q9UQ90 and Q9Y4W6)
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