AFG32_HUMAN
ID AFG32_HUMAN Reviewed; 797 AA.
AC Q9Y4W6; Q6P1L0;
DT 27-APR-2001, integrated into UniProtKB/Swiss-Prot.
DT 20-FEB-2007, sequence version 2.
DT 03-AUG-2022, entry version 205.
DE RecName: Full=AFG3-like protein 2 {ECO:0000305};
DE EC=3.4.24.- {ECO:0000269|PubMed:14623864, ECO:0000269|PubMed:22354088};
DE AltName: Full=Paraplegin-like protein;
DE Flags: Precursor;
GN Name=AFG3L2 {ECO:0000312|HGNC:HGNC:315};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND SUBCELLULAR LOCATION.
RX PubMed=10395799; DOI=10.1006/geno.1999.5818;
RA Banfi S., Bassi M.T., Andolfi G., Marchitiello A., Zanotta S., Ballabio A.,
RA Casari G., Franco B.;
RT "Identification and characterization of AFG3L2, a novel paraplegin-related
RT gene.";
RL Genomics 59:51-58(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Eye;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP INTERACTION WITH SPG7.
RX PubMed=14623864; DOI=10.1083/jcb.200304112;
RA Atorino L., Silvestri L., Koppen M., Cassina L., Ballabio A., Marconi R.,
RA Langer T., Casari G.;
RT "Loss of m-AAA protease in mitochondria causes complex I deficiency and
RT increased sensitivity to oxidative stress in hereditary spastic
RT paraplegia.";
RL J. Cell Biol. 163:777-787(2003).
RN [4]
RP SUBUNIT.
RX PubMed=17101804; DOI=10.1128/mcb.01470-06;
RA Koppen M., Metodiev M.D., Casari G., Rugarli E.I., Langer T.;
RT "Variable and tissue-specific subunit composition of mitochondrial m-AAA
RT protease complexes linked to hereditary spastic paraplegia.";
RL Mol. Cell. Biol. 27:758-767(2007).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
RX PubMed=22354088; DOI=10.1038/embor.2012.14;
RA Greene A.W., Grenier K., Aguileta M.A., Muise S., Farazifard R.,
RA Haque M.E., McBride H.M., Park D.S., Fon E.A.;
RT "Mitochondrial processing peptidase regulates PINK1 processing, import and
RT Parkin recruitment.";
RL EMBO Rep. 13:378-385(2012).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [8]
RP INTERACTION WITH SPG7.
RX PubMed=26387735; DOI=10.1016/j.molcel.2015.08.009;
RA Shanmughapriya S., Rajan S., Hoffman N.E., Higgins A.M., Tomar D.,
RA Nemani N., Hines K.J., Smith D.J., Eguchi A., Vallem S., Shaikh F.,
RA Cheung M., Leonard N.J., Stolakis R.S., Wolfers M.P., Ibetti J.,
RA Chuprun J.K., Jog N.R., Houser S.R., Koch W.J., Elrod J.W., Madesh M.;
RT "SPG7 is an essential and conserved component of the mitochondrial
RT permeability transition pore.";
RL Mol. Cell 60:47-62(2015).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [10]
RP INTERACTION WITH MAIP1.
RX PubMed=27499296; DOI=10.1016/j.molcel.2016.06.033;
RA Floyd B.J., Wilkerson E.M., Veling M.T., Minogue C.E., Xia C., Beebe E.T.,
RA Wrobel R.L., Cho H., Kremer L.S., Alston C.L., Gromek K.A., Dolan B.K.,
RA Ulbrich A., Stefely J.A., Bohl S.L., Werner K.M., Jochem A.,
RA Westphall M.S., Rensvold J.W., Taylor R.W., Prokisch H., Kim J.J.,
RA Coon J.J., Pagliarini D.J.;
RT "Mitochondrial protein interaction mapping identifies regulators of
RT respiratory chain function.";
RL Mol. Cell 63:621-632(2016).
RN [11]
RP FUNCTION, AND INTERACTION WITH MAIP1.
RX PubMed=27642048; DOI=10.1016/j.molcel.2016.08.020;
RA Koenig T., Troeder S.E., Bakka K., Korwitz A., Richter-Dennerlein R.,
RA Lampe P.A., Patron M., Muehlmeister M., Guerrero-Castillo S., Brandt U.,
RA Decker T., Lauria I., Paggio A., Rizzuto R., Rugarli E.I., De Stefani D.,
RA Langer T.;
RT "The m-AAA protease associated with neurodegeneration limits MCU activity
RT in mitochondria.";
RL Mol. Cell 64:148-162(2016).
RN [12]
RP STRUCTURE BY NMR OF 164-251.
RG Northeast structural genomics consortium (NESG);
RT "Northeast structural genomics consortium target HR6741A.";
RL Submitted (MAR-2012) to the PDB data bank.
RN [13]
RP VARIANT SCA28 LYS-700.
RX PubMed=20354562; DOI=10.1038/ejhg.2010.40;
RA Edener U., Wollner J., Hehr U., Kohl Z., Schilling S., Kreuz F., Bauer P.,
RA Bernard V., Gillessen-Kaesbach G., Zuhlke C.;
RT "Early onset and slow progression of SCA28, a rare dominant ataxia in a
RT large four-generation family with a novel AFG3L2 mutation.";
RL Eur. J. Hum. Genet. 18:965-968(2010).
RN [14]
RP VARIANTS SCA28 ILE-654; VAL-666; ARG-666; THR-666; ARG-671 AND GLU-671.
RX PubMed=20725928; DOI=10.1002/humu.21342;
RA Cagnoli C., Stevanin G., Brussino A., Barberis M., Mancini C.,
RA Margolis R.L., Holmes S.E., Nobili M., Forlani S., Padovan S., Pappi P.,
RA Zaros C., Leber I., Ribai P., Pugliese L., Assalto C., Brice A., Migone N.,
RA Durr A., Brusco A.;
RT "Missense mutations in the AFG3L2 proteolytic domain account for
RT approximately 1.5% of European autosomal dominant cerebellar ataxias.";
RL Hum. Mutat. 31:1117-1124(2010).
RN [15]
RP VARIANTS SCA28 THR-432; LYS-691; GLU-694 AND GLN-702, AND TISSUE
RP SPECIFICITY.
RX PubMed=20208537; DOI=10.1038/ng.544;
RA Di Bella D., Lazzaro F., Brusco A., Plumari M., Battaglia G., Pastore A.,
RA Finardi A., Cagnoli C., Tempia F., Frontali M., Veneziano L., Sacco T.,
RA Boda E., Brussino A., Bonn F., Castellotti B., Baratta S., Mariotti C.,
RA Gellera C., Fracasso V., Magri S., Langer T., Plevani P., Di Donato S.,
RA Muzi-Falconi M., Taroni F.;
RT "Mutations in the mitochondrial protease gene AFG3L2 cause dominant
RT hereditary ataxia SCA28.";
RL Nat. Genet. 42:313-321(2010).
RN [16]
RP VARIANT SPAX5 CYS-616, AND CHARACTERIZATION OF VARIANT SPAX5 CYS-616.
RX PubMed=22022284; DOI=10.1371/journal.pgen.1002325;
RA Pierson T.M., Adams D., Bonn F., Martinelli P., Cherukuri P.F., Teer J.K.,
RA Hansen N.F., Cruz P., Mullikin J.C., Blakesley R.W., Golas G., Kwan J.,
RA Sandler A., Fuentes Fajardo K., Markello T., Tifft C., Blackstone C.,
RA Rugarli E.I., Langer T., Gahl W.A., Toro C.;
RT "Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic
RT ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases.";
RL PLoS Genet. 7:E1002325-E1002325(2011).
RN [17]
RP VARIANT SCA28 HIS-689.
RX PubMed=24293060; DOI=10.1007/s12031-013-0187-1;
RA Loebbe A.M., Kang J.S., Hilker R., Hackstein H., Mueller U., Nolte D.;
RT "A novel missense mutation in AFG3L2 associated with late onset and slow
RT progression of spinocerebellar ataxia type 28.";
RL J. Mol. Neurosci. 52:493-496(2014).
RN [18]
RP VARIANT SCA28 ASN-689.
RX PubMed=26677414; DOI=10.1186/s40673-015-0038-7;
RA Zuehlke C., Mikat B., Timmann D., Wieczorek D., Gillessen-Kaesbach G.,
RA Buerk K.;
RT "Spinocerebellar ataxia 28: a novel AFG3L2 mutation in a German family with
RT young onset, slow progression and saccadic slowing.";
RL Cerebellum Ataxias 2:19-19(2015).
RN [19]
RP VARIANT OPA12 CYS-468, AND INVOLVEMENT IN OPA12.
RX PubMed=26539208; DOI=10.3389/fgene.2015.00311;
RA Charif M., Roubertie A., Salime S., Mamouni S., Goizet C., Hamel C.P.,
RA Lenaers G.;
RT "A novel mutation of AFG3L2 might cause dominant optic atrophy in patients
RT with mild intellectual disability.";
RL Front. Genet. 6:311-311(2015).
RN [20]
RP VARIANT OPA12 CYS-468, AND INVOLVEMENT IN OPA12.
RX PubMed=29181157; DOI=10.3892/br.2017.987;
RA Colavito D., Maritan V., Suppiej A., Del Giudice E., Mazzarolo M.,
RA Miotto S., Farina S., Dalle Carbonare M., Piermarocchi S., Leon A.;
RT "Non-syndromic isolated dominant optic atrophy caused by the p.R468C
RT mutation in the AFG3 like matrix AAA peptidase subunit 2 gene.";
RL Biomed. Rep. 7:451-454(2017).
RN [21]
RP VARIANTS SCA28 VAL-621 AND VAL-666.
RX PubMed=29053796; DOI=10.1093/brain/awx251;
RA Nibbeling E.A.R., Duarri A., Verschuuren-Bemelmans C.C., Fokkens M.R.,
RA Karjalainen J.M., Smeets C.J.L.M., de Boer-Bergsma J.J., van der Vries G.,
RA Dooijes D., Bampi G.B., van Diemen C., Brunt E., Ippel E., Kremer B.,
RA Vlak M., Adir N., Wijmenga C., van de Warrenburg B.P.C., Franke L.,
RA Sinke R.J., Verbeek D.S.;
RT "Exome sequencing and network analysis identifies shared mechanisms
RT underlying spinocerebellar ataxia.";
RL Brain 140:2860-2878(2017).
RN [22]
RP VARIANT OPA12 CYS-468, CHARACTERIZATION OF VARIANT OPA12 CYS-468,
RP CHARACTERIZATION OF VARIANT SCA28 LYS-691, MUTAGENESIS OF GLU-575,
RP FUNCTION, AND INTERACTION WITH SPG7.
RX PubMed=30252181; DOI=10.1002/humu.23658;
RA Magri S., Fracasso V., Plumari M., Alfei E., Ghezzi D., Gellera C.,
RA Rusmini P., Poletti A., Di Bella D., Elia A.E., Pantaleoni C., Taroni F.;
RT "Concurrent AFG3L2 and SPG7 mutations associated with syndromic
RT parkinsonism and optic atrophy with aberrant OPA1 processing and
RT mitochondrial network fragmentation.";
RL Hum. Mutat. 39:2060-2071(2018).
RN [23]
RP VARIANT OPA12 GLU-337, CHARACTERIZATION OF VARIANT OPA12 GLU-337, AND
RP FUNCTION.
RX PubMed=32600459; DOI=10.1186/s40478-020-00975-w;
RA Baderna V., Schultz J., Kearns L.S., Fahey M., Thompson B.A., Ruddle J.B.,
RA Huq A., Maltecca F.;
RT "A novel AFG3L2 mutation close to AAA domain leads to aberrant OMA1 and
RT OPA1 processing in a family with optic atrophy.";
RL Acta Neuropathol. Commun. 8:93-93(2020).
RN [24]
RP INVOLVEMENT IN OPA12, VARIANTS SPAX5 GLU-306; VAL-462 AND LYS-620, VARIANTS
RP OPA12 PHE-346; SER-377; GLY-407; ILE-430; VAL-462; LYS-465; LEU-514 AND
RP CYS-605, CHARACTERIZATION OF VARIANTS OPA12 GLY-407; VAL-462; LYS-465 AND
RP LEU-514, AND CHARACTERIZATION OF VARIANT SPAX5 LYS-620.
RX PubMed=32219868; DOI=10.1002/ana.25723;
RA Caporali L., Magri S., Legati A., Del Dotto V., Tagliavini F.,
RA Balistreri F., Nasca A., La Morgia C., Carbonelli M., Valentino M.L.,
RA Lamantea E., Baratta S., Schoels L., Schuele R., Barboni P.,
RA Cascavilla M.L., Maresca A., Capristo M., Ardissone A., Pareyson D.,
RA Cammarata G., Melzi L., Zeviani M., Peverelli L., Lamperti C.,
RA Marzoli S.B., Fang M., Synofzik M., Ghezzi D., Carelli V., Taroni F.;
RT "ATPase domain AFG3L2 mutations alter OPA1 processing and cause optic
RT neuropathy.";
RL Ann. Neurol. 88:18-32(2020).
RN [25]
RP VARIANTS OPA12 ALA-74; ARG-337; GLU-337; LYS-376; SER-416; LEU-514 AND
RP SER-644.
RX PubMed=32548275; DOI=10.1212/nxg.0000000000000428;
RA Charif M., Chevrollier A., Gueguen N., Bris C., Goudenege D.,
RA Desquiret-Dumas V., Leruez S., Colin E., Meunier A., Vignal C., Smirnov V.,
RA Defoort-Dhellemmes S., Drumare Bouvet I., Goizet C., Votruba M.,
RA Jurkute N., Yu-Wai-Man P., Tagliavini F., Caporali L., La Morgia C.,
RA Carelli V., Procaccio V., Zanlonghi X., Meunier I., Reynier P., Bonneau D.,
RA Amati-Bonneau P., Lenaers G.;
RT "Mutations in the m-AAA proteases AFG3L2 and SPG7 are causing isolated
RT dominant optic atrophy.";
RL Neurol. Genet. 6:e428-e428(2020).
CC -!- FUNCTION: ATP-dependent protease which is essential for axonal and
CC neuron development. In neurons, mediates degradation of SMDT1/EMRE
CC before its assembly with the uniporter complex, limiting the
CC availability of SMDT1/EMRE for MCU assembly and promoting efficient
CC assembly of gatekeeper subunits with MCU (PubMed:27642048). Required
CC for paraplegin (SPG7) maturation (PubMed:30252181). After its cleavage
CC by mitochondrial-processing peptidase (MPP), it converts paraplegin
CC into a proteolytically active mature form (By similarity). Required for
CC the maturation of PINK1 into its 52kDa mature form after its cleavage
CC by mitochondrial-processing peptidase (MPP) (PubMed:22354088,
CC PubMed:30252181). Involved in the regulation of OMA1-dependent
CC processing of OPA1 (PubMed:32600459, PubMed:30252181).
CC {ECO:0000250|UniProtKB:Q8JZQ2, ECO:0000269|PubMed:22354088,
CC ECO:0000269|PubMed:27642048, ECO:0000269|PubMed:30252181,
CC ECO:0000269|PubMed:32600459}.
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000250|UniProtKB:Q9WZ49};
CC Note=Binds 1 zinc ion per subunit. {ECO:0000250|UniProtKB:Q9WZ49};
CC -!- SUBUNIT: Homooligomer. Forms heterooligomers with SPG7 and AFG3L1
CC (PubMed:17101804). Interacts with SPG7; the interaction is required for
CC the efficient assembly of mitochondrial complex I (PubMed:14623864,
CC PubMed:26387735, PubMed:30252181). Interacts with AFG3L1 (By
CC similarity). Interacts with MAIP1 (PubMed:27499296, PubMed:27642048).
CC Interacts with DNAJC19 and PHB2 (By similarity).
CC {ECO:0000250|UniProtKB:Q8JZQ2, ECO:0000269|PubMed:14623864,
CC ECO:0000269|PubMed:17101804, ECO:0000269|PubMed:26387735,
CC ECO:0000269|PubMed:27499296, ECO:0000269|PubMed:27642048,
CC ECO:0000269|PubMed:30252181}.
CC -!- INTERACTION:
CC Q9Y4W6; P42858: HTT; NbExp=3; IntAct=EBI-358755, EBI-466029;
CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:10395799,
CC ECO:0000269|PubMed:22354088}. Mitochondrion inner membrane
CC {ECO:0000250|UniProtKB:Q8JZQ2}; Multi-pass membrane protein
CC {ECO:0000255}.
CC -!- TISSUE SPECIFICITY: Ubiquitous. Highly expressed in the cerebellar
CC Purkinje cells. {ECO:0000269|PubMed:20208537}.
CC -!- PTM: Upon import into the mitochondrion, the N-terminal transit peptide
CC is cleaved to generate an intermediate form which undergoes
CC autocatalytic proteolytic processing to generate the proteolytically
CC active mature form. {ECO:0000250|UniProtKB:Q8JZQ2,
CC ECO:0000269|PubMed:30252181}.
CC -!- DISEASE: Spinocerebellar ataxia 28 (SCA28) [MIM:610246]:
CC Spinocerebellar ataxia is a clinically and genetically heterogeneous
CC group of cerebellar disorders. Patients show progressive incoordination
CC of gait and often poor coordination of hands, speech and eye movements,
CC due to degeneration of the cerebellum with variable involvement of the
CC brainstem and spinal cord. SCA28 is an autosomal dominant cerebellar
CC ataxia (ADCA) with a slow progressive course and no evidence of sensory
CC involvement or cognitive impairment. {ECO:0000269|PubMed:20208537,
CC ECO:0000269|PubMed:20354562, ECO:0000269|PubMed:20725928,
CC ECO:0000269|PubMed:24293060, ECO:0000269|PubMed:26677414,
CC ECO:0000269|PubMed:29053796, ECO:0000269|PubMed:30252181}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Spastic ataxia 5, autosomal recessive (SPAX5) [MIM:614487]: A
CC neurodegenerative disorder characterized by early onset spasticity,
CC peripheral neuropathy, ptosis, oculomotor apraxia, dystonia, cerebellar
CC atrophy, and progressive myoclonic epilepsy.
CC {ECO:0000269|PubMed:22022284, ECO:0000269|PubMed:32219868}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Optic atrophy 12 (OPA12) [MIM:618977]: An autosomal dominant
CC disease characterized by progressive visual loss in association with
CC optic atrophy. Atrophy of the optic disk indicates a deficiency in the
CC number of nerve fibers which arise in the retina and converge to form
CC the optic disk, optic nerve, optic chiasm and optic tracts. OPA12
CC patients manifest slowly progressive visual impairment with onset
CC usually in the first decade. Some patients may exhibit additional
CC features including impaired intellectual development, dystonia,
CC movement disorders, or ataxia. {ECO:0000269|PubMed:26539208,
CC ECO:0000269|PubMed:29181157, ECO:0000269|PubMed:30252181,
CC ECO:0000269|PubMed:32219868, ECO:0000269|PubMed:32548275,
CC ECO:0000269|PubMed:32600459}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: In the N-terminal section; belongs to the AAA ATPase
CC family. {ECO:0000305}.
CC -!- SIMILARITY: In the C-terminal section; belongs to the peptidase M41
CC family. {ECO:0000305}.
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DR EMBL; Y18314; CAB48398.1; -; mRNA.
DR EMBL; BC065016; AAH65016.1; -; mRNA.
DR CCDS; CCDS11859.1; -.
DR RefSeq; NP_006787.2; NM_006796.2.
DR PDB; 2LNA; NMR; -; A=164-251.
DR PDB; 6NYY; EM; 3.00 A; A/B/C/D/E/F=272-797.
DR PDBsum; 2LNA; -.
DR PDBsum; 6NYY; -.
DR AlphaFoldDB; Q9Y4W6; -.
DR BMRB; Q9Y4W6; -.
DR SMR; Q9Y4W6; -.
DR BioGRID; 116139; 326.
DR CORUM; Q9Y4W6; -.
DR IntAct; Q9Y4W6; 91.
DR MINT; Q9Y4W6; -.
DR STRING; 9606.ENSP00000269143; -.
DR BindingDB; Q9Y4W6; -.
DR ChEMBL; CHEMBL4802020; -.
DR DrugBank; DB00171; ATP.
DR MEROPS; M41.007; -.
DR GlyGen; Q9Y4W6; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q9Y4W6; -.
DR MetOSite; Q9Y4W6; -.
DR PhosphoSitePlus; Q9Y4W6; -.
DR SwissPalm; Q9Y4W6; -.
DR BioMuta; AFG3L2; -.
DR DMDM; 126302516; -.
DR EPD; Q9Y4W6; -.
DR jPOST; Q9Y4W6; -.
DR MassIVE; Q9Y4W6; -.
DR MaxQB; Q9Y4W6; -.
DR PaxDb; Q9Y4W6; -.
DR PeptideAtlas; Q9Y4W6; -.
DR PRIDE; Q9Y4W6; -.
DR ProteomicsDB; 86254; -.
DR TopDownProteomics; Q9Y4W6; -.
DR Antibodypedia; 1387; 274 antibodies from 31 providers.
DR DNASU; 10939; -.
DR Ensembl; ENST00000269143.8; ENSP00000269143.2; ENSG00000141385.12.
DR GeneID; 10939; -.
DR KEGG; hsa:10939; -.
DR MANE-Select; ENST00000269143.8; ENSP00000269143.2; NM_006796.3; NP_006787.2.
DR UCSC; uc002kqz.3; human.
DR CTD; 10939; -.
DR DisGeNET; 10939; -.
DR GeneCards; AFG3L2; -.
DR GeneReviews; AFG3L2; -.
DR HGNC; HGNC:315; AFG3L2.
DR HPA; ENSG00000141385; Low tissue specificity.
DR MalaCards; AFG3L2; -.
DR MIM; 604581; gene.
DR MIM; 610246; phenotype.
DR MIM; 614487; phenotype.
DR MIM; 618977; phenotype.
DR neXtProt; NX_Q9Y4W6; -.
DR OpenTargets; ENSG00000141385; -.
DR Orphanet; 313772; Early-onset spastic ataxia-myoclonic epilepsy-neuropathy syndrome.
DR Orphanet; 101109; Spinocerebellar ataxia type 28.
DR PharmGKB; PA24612; -.
DR VEuPathDB; HostDB:ENSG00000141385; -.
DR eggNOG; KOG0731; Eukaryota.
DR GeneTree; ENSGT00940000159566; -.
DR HOGENOM; CLU_000688_23_1_1; -.
DR InParanoid; Q9Y4W6; -.
DR OMA; DEAYKQC; -.
DR OrthoDB; 217929at2759; -.
DR PhylomeDB; Q9Y4W6; -.
DR TreeFam; TF105004; -.
DR BRENDA; 3.4.24.B18; 2681.
DR PathwayCommons; Q9Y4W6; -.
DR Reactome; R-HSA-8949664; Processing of SMDT1.
DR SignaLink; Q9Y4W6; -.
DR BioGRID-ORCS; 10939; 719 hits in 1101 CRISPR screens.
DR ChiTaRS; AFG3L2; human.
DR GeneWiki; AFG3L2; -.
DR GenomeRNAi; 10939; -.
DR Pharos; Q9Y4W6; Tbio.
DR PRO; PR:Q9Y4W6; -.
DR Proteomes; UP000005640; Chromosome 18.
DR RNAct; Q9Y4W6; protein.
DR Bgee; ENSG00000141385; Expressed in Brodmann (1909) area 23 and 196 other tissues.
DR ExpressionAtlas; Q9Y4W6; baseline and differential.
DR Genevisible; Q9Y4W6; HS.
DR GO; GO:0005745; C:m-AAA complex; IBA:GO_Central.
DR GO; GO:0005743; C:mitochondrial inner membrane; ISS:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0016887; F:ATP hydrolysis activity; IEA:InterPro.
DR GO; GO:0004176; F:ATP-dependent peptidase activity; IEA:InterPro.
DR GO; GO:0004222; F:metalloendopeptidase activity; IDA:UniProtKB.
DR GO; GO:0008237; F:metallopeptidase activity; IMP:UniProtKB.
DR GO; GO:0051082; F:unfolded protein binding; TAS:ProtInc.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0007409; P:axonogenesis; IMP:UniProtKB.
DR GO; GO:0036444; P:calcium import into the mitochondrion; IMP:UniProtKB.
DR GO; GO:0042407; P:cristae formation; IEA:Ensembl.
DR GO; GO:0033619; P:membrane protein proteolysis; IDA:UniProtKB.
DR GO; GO:0051560; P:mitochondrial calcium ion homeostasis; IMP:UniProtKB.
DR GO; GO:0008053; P:mitochondrial fusion; IEA:Ensembl.
DR GO; GO:0034982; P:mitochondrial protein processing; IBA:GO_Central.
DR GO; GO:0055001; P:muscle cell development; IEA:Ensembl.
DR GO; GO:0042552; P:myelination; IEA:Ensembl.
DR GO; GO:0021675; P:nerve development; IEA:Ensembl.
DR GO; GO:0007528; P:neuromuscular junction development; IEA:Ensembl.
DR GO; GO:0016540; P:protein autoprocessing; ISS:UniProtKB.
DR GO; GO:0016485; P:protein processing; ISS:UniProtKB.
DR GO; GO:0065003; P:protein-containing complex assembly; IBA:GO_Central.
DR GO; GO:0006508; P:proteolysis; IMP:UniProtKB.
DR GO; GO:0040014; P:regulation of multicellular organism growth; IEA:Ensembl.
DR GO; GO:0060013; P:righting reflex; IEA:Ensembl.
DR Gene3D; 1.20.58.760; -; 1.
DR Gene3D; 3.40.50.300; -; 1.
DR HAMAP; MF_01458; FtsH; 1.
DR InterPro; IPR003593; AAA+_ATPase.
DR InterPro; IPR041569; AAA_lid_3.
DR InterPro; IPR003959; ATPase_AAA_core.
DR InterPro; IPR003960; ATPase_AAA_CS.
DR InterPro; IPR005936; FtsH.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR011546; Pept_M41_FtsH_extracell.
DR InterPro; IPR000642; Peptidase_M41.
DR InterPro; IPR037219; Peptidase_M41-like.
DR Pfam; PF00004; AAA; 1.
DR Pfam; PF17862; AAA_lid_3; 1.
DR Pfam; PF06480; FtsH_ext; 1.
DR Pfam; PF01434; Peptidase_M41; 1.
DR SMART; SM00382; AAA; 1.
DR SUPFAM; SSF140990; SSF140990; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR TIGRFAMs; TIGR01241; FtsH_fam; 1.
DR PROSITE; PS00674; AAA; 1.
PE 1: Evidence at protein level;
KW 3D-structure; ATP-binding; Disease variant; Hydrolase; Membrane;
KW Metal-binding; Metalloprotease; Mitochondrion;
KW Mitochondrion inner membrane; Neurodegeneration; Nucleotide-binding;
KW Protease; Reference proteome; Spinocerebellar ataxia; Transit peptide;
KW Transmembrane; Transmembrane helix; Zinc.
FT TRANSIT 1..38
FT /note="Mitochondrion"
FT /evidence="ECO:0000250|UniProtKB:Q8JZQ2"
FT PROPEP 39..66
FT /note="Removed in mature form"
FT /evidence="ECO:0000250|UniProtKB:Q8JZQ2"
FT /id="PRO_0000442311"
FT CHAIN 67..797
FT /note="AFG3-like protein 2"
FT /id="PRO_0000442312"
FT TRANSMEM 143..163
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 251..271
FT /note="Helical"
FT /evidence="ECO:0000255"
FT REGION 76..126
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 759..797
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 84..102
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 771..797
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 575
FT /evidence="ECO:0000250|UniProtKB:Q9WZ49"
FT BINDING 348..355
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255"
FT BINDING 574
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:Q9WZ49"
FT BINDING 578
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:Q9WZ49"
FT BINDING 649
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:Q9WZ49"
FT MOD_RES 117
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q8JZQ2"
FT VARIANT 74
FT /note="E -> A (in OPA12; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:32548275"
FT /id="VAR_084603"
FT VARIANT 306
FT /note="K -> E (in SPAX5; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:32219868"
FT /id="VAR_084604"
FT VARIANT 337
FT /note="G -> E (in OPA12; loss-of-function variant resulting
FT in aberrant OPA1 processing and mitochondrial
FT fragmentation)"
FT /evidence="ECO:0000269|PubMed:32548275,
FT ECO:0000269|PubMed:32600459"
FT /id="VAR_084605"
FT VARIANT 337
FT /note="G -> R (in OPA12)"
FT /evidence="ECO:0000269|PubMed:32548275"
FT /id="VAR_084606"
FT VARIANT 346
FT /note="L -> F (in OPA12; unknown pathological significance;
FT dbSNP:rs755893615)"
FT /evidence="ECO:0000269|PubMed:32219868"
FT /id="VAR_084607"
FT VARIANT 376
FT /note="E -> K (in OPA12; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:32548275"
FT /id="VAR_084608"
FT VARIANT 377
FT /note="F -> S (in OPA12; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:32219868"
FT /id="VAR_084609"
FT VARIANT 407
FT /note="D -> G (in OPA12; unknown pathological significance;
FT decreased proteolytic function)"
FT /evidence="ECO:0000269|PubMed:32219868"
FT /id="VAR_084610"
FT VARIANT 416
FT /note="R -> S (in OPA12; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:32548275"
FT /id="VAR_084611"
FT VARIANT 430
FT /note="T -> I (in OPA12; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:32219868"
FT /id="VAR_084612"
FT VARIANT 432
FT /note="N -> T (in SCA28; dbSNP:rs151344512)"
FT /evidence="ECO:0000269|PubMed:20208537"
FT /id="VAR_063544"
FT VARIANT 462
FT /note="A -> V (in OPA12 and SPAX5; decreased proteolytic
FT function; dbSNP:rs912546325)"
FT /evidence="ECO:0000269|PubMed:32219868"
FT /id="VAR_084613"
FT VARIANT 465
FT /note="R -> K (in OPA12; decreased proteolytic function)"
FT /evidence="ECO:0000269|PubMed:32219868"
FT /id="VAR_084614"
FT VARIANT 468
FT /note="R -> C (in OPA12; decreased proteolytic function
FT resulting in impaired autocatalytic processing and impaired
FT proteolytic maturation of SPG7; does not affect the
FT interaction with SPG7; dbSNP:rs1020764190)"
FT /evidence="ECO:0000269|PubMed:26539208,
FT ECO:0000269|PubMed:29181157, ECO:0000269|PubMed:30252181"
FT /id="VAR_084615"
FT VARIANT 514
FT /note="P -> L (in OPA12; decreased proteolytic function)"
FT /evidence="ECO:0000269|PubMed:32219868,
FT ECO:0000269|PubMed:32548275"
FT /id="VAR_084616"
FT VARIANT 605
FT /note="Y -> C (in OPA12; unknown pathological significance;
FT dbSNP:rs773240455)"
FT /evidence="ECO:0000269|PubMed:32219868"
FT /id="VAR_084617"
FT VARIANT 616
FT /note="Y -> C (in SPAX5; hypomorphic mutation; results in
FT impaired oligomerization with itself and SPG7; retains
FT ATPase and proteolytic activities; dbSNP:rs387906889)"
FT /evidence="ECO:0000269|PubMed:22022284"
FT /id="VAR_067330"
FT VARIANT 620
FT /note="Q -> K (in SPAX5; impaired function shown in a yeast
FT complementation assay)"
FT /evidence="ECO:0000269|PubMed:32219868"
FT /id="VAR_084618"
FT VARIANT 621
FT /note="L -> V (in SCA28; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:29053796"
FT /id="VAR_080736"
FT VARIANT 644
FT /note="T -> S (in OPA12; unknown pathological significance;
FT dbSNP:rs1226952405)"
FT /evidence="ECO:0000269|PubMed:32548275"
FT /id="VAR_084619"
FT VARIANT 654
FT /note="T -> I (in SCA28; dbSNP:rs151344513)"
FT /evidence="ECO:0000269|PubMed:20725928"
FT /id="VAR_064402"
FT VARIANT 666
FT /note="M -> R (in SCA28; dbSNP:rs151344515)"
FT /evidence="ECO:0000269|PubMed:20725928"
FT /id="VAR_064403"
FT VARIANT 666
FT /note="M -> T (in SCA28; dbSNP:rs151344515)"
FT /evidence="ECO:0000269|PubMed:20725928"
FT /id="VAR_064404"
FT VARIANT 666
FT /note="M -> V (in SCA28; dbSNP:rs151344514)"
FT /evidence="ECO:0000269|PubMed:20725928,
FT ECO:0000269|PubMed:29053796"
FT /id="VAR_064405"
FT VARIANT 671
FT /note="G -> E (in SCA28; dbSNP:rs151344518)"
FT /evidence="ECO:0000269|PubMed:20725928"
FT /id="VAR_064406"
FT VARIANT 671
FT /note="G -> R (in SCA28; dbSNP:rs151344517)"
FT /evidence="ECO:0000269|PubMed:20725928"
FT /id="VAR_064407"
FT VARIANT 689
FT /note="Y -> H (in SCA28; dbSNP:rs1598820860)"
FT /evidence="ECO:0000269|PubMed:24293060"
FT /id="VAR_075198"
FT VARIANT 689
FT /note="Y -> N (in SCA28)"
FT /evidence="ECO:0000269|PubMed:26677414"
FT /id="VAR_075199"
FT VARIANT 691
FT /note="E -> K (in SCA28; impaired function shown in a yeast
FT complementation assay; dbSNP:rs151344520)"
FT /evidence="ECO:0000269|PubMed:20208537,
FT ECO:0000269|PubMed:30252181"
FT /id="VAR_063545"
FT VARIANT 694
FT /note="A -> E (in SCA28; dbSNP:rs151344521)"
FT /evidence="ECO:0000269|PubMed:20208537"
FT /id="VAR_063546"
FT VARIANT 700
FT /note="E -> K (in SCA28; dbSNP:rs151344522)"
FT /evidence="ECO:0000269|PubMed:20354562"
FT /id="VAR_064408"
FT VARIANT 702
FT /note="R -> Q (in SCA28; dbSNP:rs151344523)"
FT /evidence="ECO:0000269|PubMed:20208537"
FT /id="VAR_063547"
FT MUTAGEN 575
FT /note="E->Q: Loss of autocatalytic processing. Impaired
FT proteolytic maturation of SPG7."
FT /evidence="ECO:0000269|PubMed:30252181"
FT CONFLICT 74
FT /note="E -> G (in Ref. 1; CAB48398)"
FT /evidence="ECO:0000305"
FT CONFLICT 633
FT /note="V -> A (in Ref. 1; CAB48398)"
FT /evidence="ECO:0000305"
FT STRAND 165..169
FT /evidence="ECO:0007829|PDB:2LNA"
FT HELIX 172..178
FT /evidence="ECO:0007829|PDB:2LNA"
FT HELIX 180..182
FT /evidence="ECO:0007829|PDB:2LNA"
FT STRAND 185..191
FT /evidence="ECO:0007829|PDB:2LNA"
FT TURN 192..194
FT /evidence="ECO:0007829|PDB:2LNA"
FT STRAND 195..200
FT /evidence="ECO:0007829|PDB:2LNA"
FT TURN 202..204
FT /evidence="ECO:0007829|PDB:2LNA"
FT STRAND 212..215
FT /evidence="ECO:0007829|PDB:2LNA"
FT HELIX 219..232
FT /evidence="ECO:0007829|PDB:2LNA"
FT TURN 237..239
FT /evidence="ECO:0007829|PDB:2LNA"
FT STRAND 243..245
FT /evidence="ECO:0007829|PDB:2LNA"
FT STRAND 297..299
FT /evidence="ECO:0007829|PDB:6NYY"
FT HELIX 307..309
FT /evidence="ECO:0007829|PDB:6NYY"
FT TURN 315..317
FT /evidence="ECO:0007829|PDB:6NYY"
FT HELIX 318..328
FT /evidence="ECO:0007829|PDB:6NYY"
FT TURN 332..337
FT /evidence="ECO:0007829|PDB:6NYY"
FT STRAND 344..347
FT /evidence="ECO:0007829|PDB:6NYY"
FT HELIX 356..364
FT /evidence="ECO:0007829|PDB:6NYY"
FT STRAND 369..373
FT /evidence="ECO:0007829|PDB:6NYY"
FT HELIX 374..376
FT /evidence="ECO:0007829|PDB:6NYY"
FT HELIX 385..398
FT /evidence="ECO:0007829|PDB:6NYY"
FT STRAND 403..408
FT /evidence="ECO:0007829|PDB:6NYY"
FT HELIX 409..411
FT /evidence="ECO:0007829|PDB:6NYY"
FT HELIX 422..439
FT /evidence="ECO:0007829|PDB:6NYY"
FT TURN 440..442
FT /evidence="ECO:0007829|PDB:6NYY"
FT STRAND 443..445
FT /evidence="ECO:0007829|PDB:6NYY"
FT STRAND 450..452
FT /evidence="ECO:0007829|PDB:6NYY"
FT STRAND 457..459
FT /evidence="ECO:0007829|PDB:6NYY"
FT TURN 461..464
FT /evidence="ECO:0007829|PDB:6NYY"
FT HELIX 480..490
FT /evidence="ECO:0007829|PDB:6NYY"
FT HELIX 504..512
FT /evidence="ECO:0007829|PDB:6NYY"
FT HELIX 518..525
FT /evidence="ECO:0007829|PDB:6NYY"
FT HELIX 527..532
FT /evidence="ECO:0007829|PDB:6NYY"
FT TURN 533..536
FT /evidence="ECO:0007829|PDB:6NYY"
FT HELIX 543..552
FT /evidence="ECO:0007829|PDB:6NYY"
FT HELIX 565..584
FT /evidence="ECO:0007829|PDB:6NYY"
FT STRAND 585..588
FT /evidence="ECO:0007829|PDB:6NYY"
FT STRAND 591..595
FT /evidence="ECO:0007829|PDB:6NYY"
FT STRAND 605..608
FT /evidence="ECO:0007829|PDB:6NYY"
FT HELIX 618..628
FT /evidence="ECO:0007829|PDB:6NYY"
FT HELIX 630..637
FT /evidence="ECO:0007829|PDB:6NYY"
FT HELIX 647..661
FT /evidence="ECO:0007829|PDB:6NYY"
FT STRAND 668..670
FT /evidence="ECO:0007829|PDB:6NYY"
FT STRAND 679..681
FT /evidence="ECO:0007829|PDB:6NYY"
FT HELIX 691..718
FT /evidence="ECO:0007829|PDB:6NYY"
FT HELIX 720..733
FT /evidence="ECO:0007829|PDB:6NYY"
FT HELIX 738..745
FT /evidence="ECO:0007829|PDB:6NYY"
FT HELIX 756..759
FT /evidence="ECO:0007829|PDB:6NYY"
FT TURN 761..763
FT /evidence="ECO:0007829|PDB:6NYY"
SQ SEQUENCE 797 AA; 88584 MW; EACBB7C5F2EE5E08 CRC64;
MAHRCLRLWG RGGCWPRGLQ QLLVPGGVGP GEQPCLRTLY RFVTTQARAS RNSLLTDIIA
AYQRFCSRPP KGFEKYFPNG KNGKKASEPK EVMGEKKESK PAATTRSSGG GGGGGGKRGG
KKDDSHWWSR FQKGDIPWDD KDFRMFFLWT ALFWGGVMFY LLLKRSGREI TWKDFVNNYL
SKGVVDRLEV VNKRFVRVTF TPGKTPVDGQ YVWFNIGSVD TFERNLETLQ QELGIEGENR
VPVVYIAESD GSFLLSMLPT VLIIAFLLYT IRRGPAGIGR TGRGMGGLFS VGETTAKVLK
DEIDVKFKDV AGCEEAKLEI MEFVNFLKNP KQYQDLGAKI PKGAILTGPP GTGKTLLAKA
TAGEANVPFI TVSGSEFLEM FVGVGPARVR DLFALARKNA PCILFIDEID AVGRKRGRGN
FGGQSEQENT LNQLLVEMDG FNTTTNVVIL AGTNRPDILD PALLRPGRFD RQIFIGPPDI
KGRASIFKVH LRPLKLDSTL EKDKLARKLA SLTPGFSGAD VANVCNEAAL IAARHLSDSI
NQKHFEQAIE RVIGGLEKKT QVLQPEEKKT VAYHEAGHAV AGWYLEHADP LLKVSIIPRG
KGLGYAQYLP KEQYLYTKEQ LLDRMCMTLG GRVSEEIFFG RITTGAQDDL RKVTQSAYAQ
IVQFGMNEKV GQISFDLPRQ GDMVLEKPYS EATARLIDDE VRILINDAYK RTVALLTEKK
ADVEKVALLL LEKEVLDKND MVELLGPRPF AEKSTYEEFV EGTGSLDEDT SLPEGLKDWN
KEREKEKEEP PGEKVAN
