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 28-JAN-2026, entry version 222. DE RecName: Full=Mitochondrial inner membrane m-AAA protease component AFG3L2 {ECO:0000305}; DE EC=3.4.24.- {ECO:0000269|PubMed:14623864, ECO:0000269|PubMed:19748354, ECO:0000269|PubMed:22354088, ECO:0000269|PubMed:29932645, ECO:0000269|PubMed:31327635, ECO:0000269|PubMed:37917749, ECO:0000269|PubMed:38157846}; DE EC=3.6.-.- {ECO:0000269|PubMed:19748354, ECO:0000269|PubMed:31327635}; DE AltName: Full=AFG3-like protein 2 {ECO:0000305}; DE AltName: Full=Paraplegin-like protein; DE Flags: Precursor; GN Name=AFG3L2 {ECO:0000303|PubMed:10395799, 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 FUNCTION. RX PubMed=17615298; DOI=10.1091/mbc.e07-02-0164; RA Duvezin-Caubet S., Koppen M., Wagener J., Zick M., Israel L., RA Bernacchia A., Jagasia R., Rugarli E.I., Imhof A., Neupert W., Langer T., RA Reichert A.S.; RT "OPA1 processing reconstituted in yeast depends on the subunit composition RT of the m-AAA protease in mitochondria."; RL Mol. Biol. Cell 18:3582-3590(2007). RN [5] 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 [6] RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF LYS-354 AND GLU-408. RX PubMed=19748354; DOI=10.1016/j.molcel.2009.07.018; RA Augustin S., Gerdes F., Lee S., Tsai F.T., Langer T., Tatsuta T.; RT "An intersubunit signaling network coordinates ATP hydrolysis by m-AAA RT proteases."; RL Mol. Cell 35:574-585(2009). RN [7] 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 [8] 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 [9] RP INVOLVEMENT IN SCA28. RX PubMed=24272953; DOI=10.1007/s12311-013-0538-z; RA Musova Z., Kaiserova M., Kriegova E., Fillerova R., Vasovcak P., RA Santava A., Mensikova K., Zumrova A., Krepelova A., Sedlacek Z., RA Kanovsky P.; RT "A novel frameshift mutation in the AFG3L2 gene in a patient with RT spinocerebellar ataxia."; RL Cerebellum 13:331-337(2014). RN [10] RP INVOLVEMENT IN SCA28. RX PubMed=24814845; DOI=10.1212/wnl.0000000000000491; RA Smets K., Deconinck T., Baets J., Sieben A., Martin J.J., Smouts I., RA Wang S., Taroni F., Di Bella D., Van Hecke W., Parizel P.M., Jadoul C., RA De Potter R., Couvreur F., Rugarli E., De Jonghe P.; RT "Partial deletion of AFG3L2 causing spinocerebellar ataxia type 28."; RL Neurology 82:2092-2100(2014). RN [11] 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 [12] RP FUNCTION. RX PubMed=26504172; DOI=10.1083/jcb.201504062; RA Richter U., Lahtinen T., Marttinen P., Suomi F., Battersby B.J.; RT "Quality control of mitochondrial protein synthesis is required for RT membrane integrity and cell fitness."; RL J. Cell Biol. 211:373-389(2015). RN [13] 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 [14] 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 [15] 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 [16] 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 [17] RP FUNCTION, AND IDENTIFICATION IN THE M-AAA PROTEASE COMPLEX. RX PubMed=28396416; DOI=10.1073/pnas.1702938114; RA Tsai C.W., Wu Y., Pao P.C., Phillips C.B., Williams C., Miller C., RA Ranaghan M., Tsai M.F.; RT "Proteolytic control of the mitochondrial calcium uniporter complex."; RL Proc. Natl. Acad. Sci. U.S.A. 114:4388-4393(2017). RN [18] RP FUNCTION, SUBUNIT, AND MUTAGENESIS OF GLU-408 AND GLU-575. RX PubMed=29932645; DOI=10.1021/acs.biochem.8b00565; RA Ding B., Martin D.W., Rampello A.J., Glynn S.E.; RT "Dissecting substrate specificities of the mitochondrial AFG3L2 protease."; RL Biochemistry 57:4225-4235(2018). RN [19] RP FUNCTION. RX PubMed=29545505; DOI=10.1242/jcs.213546; RA Consolato F., Maltecca F., Tulli S., Sambri I., Casari G.; RT "m-AAA and i-AAA complexes coordinate to regulate OMA1, the stress- RT activated supervisor of mitochondrial dynamics."; RL J. Cell Sci. 131:0-0(2018). RN [20] RP FUNCTION. RX PubMed=30683687; DOI=10.26508/lsa.201800219; RA Richter U., Ng K.Y., Suomi F., Marttinen P., Turunen T., Jackson C., RA Suomalainen A., Vihinen H., Jokitalo E., Nyman T.A., Isokallio M.A., RA Stewart J.B., Mancini C., Brusco A., Seneca S., Lombes A., Taylor R.W., RA Battersby B.J.; RT "Mitochondrial stress response triggered by defects in protein synthesis RT quality control."; RL Life. Sci Alliance 2:0-0(2019). RN [21] RP FUNCTION. RX PubMed=35912435; DOI=10.15252/embj.2021110476; RA Patron M., Tarasenko D., Nolte H., Kroczek L., Ghosh M., Ohba Y., RA Lasarzewski Y., Ahmadi Z.A., Cabrera-Orefice A., Eyiama A., Kellermann T., RA Rugarli E.I., Brandt U., Meinecke M., Langer T.; RT "Regulation of mitochondrial proteostasis by the proton gradient."; RL EMBO J. 41:e110476-e110476(2022). RN [22] RP FUNCTION. RX PubMed=34718584; DOI=10.1093/hmg/ddab314; RA Ng K.Y., Richter U., Jackson C.B., Seneca S., Battersby B.J.; RT "Translation of MT-ATP6 pathogenic variants reveals distinct regulatory RT consequences from the co-translational quality control of mitochondrial RT protein synthesis."; RL Hum. Mol. Genet. 31:1230-1241(2022). RN [23] RP FUNCTION. RX PubMed=38157846; DOI=10.1016/j.molcel.2023.12.008; RA Shi X., DeCiucis M., Grabinska K.A., Kanyo J., Liu A., Lam T.T., Shen H.; RT "Dual regulation of SLC25A39 by AFG3L2 and iron controls mitochondrial RT glutathione homeostasis."; RL Mol. Cell 0:0-0(2023). RN [24] RP FUNCTION, AND MUTAGENESIS OF GLU-408. RX PubMed=37917749; DOI=10.1126/science.adf4154; RA Liu Y., Liu S., Tomar A., Yen F.S., Unlu G., Ropek N., Weber R.A., Wang Y., RA Khan A., Gad M., Peng J., Terzi E., Alwaseem H., Pagano A.E., Heissel S., RA Molina H., Allwein B., Kenny T.C., Possemato R.L., Zhao L., Hite R.K., RA Vinogradova E.V., Mansy S.S., Birsoy K.; RT "Autoregulatory control of mitochondrial glutathione homeostasis."; RL Science 382:820-828(2023). RN [25] {ECO:0007744|PDB:2LNA} RP STRUCTURE BY NMR OF 164-251, AND SUBUNIT. RX PubMed=24055473; DOI=10.1016/j.febslet.2013.09.009; RA Ramelot T.A., Yang Y., Sahu I.D., Lee H.W., Xiao R., Lorigan G.A., RA Montelione G.T., Kennedy M.A.; RT "NMR structure and MD simulations of the AAA protease intermembrane space RT domain indicates peripheral membrane localization within the RT hexaoligomer."; RL FEBS Lett. 587:3522-3528(2013). RN [26] {ECO:0007744|PDB:6NYY} RP STRUCTURE BY ELECTRON MICROSCOPY (3.00 ANGSTROMS) OF 272-797 IN COMPLEX RP WITH ZINC; ADP AND PEPTIDE SUBSTRATE, FUNCTION, CATALYTIC ACTIVITY, RP COFACTOR, SUBUNIT, SUBCELLULAR LOCATION, MUTAGENESIS OF PHE-289; LEU-299; RP MET-380; PHE-421; GLU-575 AND TRP-779, CHARACTERIZATION OF VARIANTS SCA28 RP THR-432; CYS-616; ARG-666 AND THR-688, AND CHARACTERIZATION OF VARIANT RP THR-572. RX PubMed=31327635; DOI=10.1016/j.molcel.2019.06.016; RA Puchades C., Ding B., Song A., Wiseman R.L., Lander G.C., Glynn S.E.; RT "Unique structural features of the mitochondrial AAA+ protease AFG3L2 RT reveal the molecular basis for activity in health and disease."; RL Mol. Cell 75:1073-1085(2019). RN [27] 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 [28] 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 [29] 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 [30] 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 [31] 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 [32] 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 [33] 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 [34] RP VARIANT SCA28 ILE-191. RX PubMed=26454370; DOI=10.1016/j.jns.2015.10.003; RA Qu J., Wu C.K., Zuzuarregui J.R., Hohler A.D.; RT "A novel AFG3L2 mutation in a Somalian patient with spinocerebellar ataxia RT type 28."; RL J. Neurol. Sci. 358:530-531(2015). RN [35] 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 [36] 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 [37] RP VARIANT SCA28 THR-688. RX PubMed=26868664; DOI=10.1007/s12311-016-0765-1; RA Svenstrup K., Nielsen T.T., Aidt F., Rostgaard N., Duno M., Wibrand F., RA Vinther-Jensen T., Law I., Vissing J., Roos P., Hjermind L.E., RA Nielsen J.E.; RT "SCA28: Novel mutation in the AFG3L2 proteolytic domain causes a mild RT cerebellar syndrome with selective type-1 muscle fiber atrophy."; RL Cerebellum 16:62-67(2017). RN [38] RP VARIANT SCA28 ARG-671. RX PubMed=28660440; DOI=10.1007/s12311-017-0870-9; RA Szpisjak L., Nemeth V.L., Szepfalusi N., Zadori D., Maroti Z., Kalmar T., RA Vecsei L., Klivenyi P.; RT "Neurocognitive characterization of an SCA28 family caused by a novel RT AFG3L2 gene mutation."; RL Cerebellum 16:979-985(2017). RN [39] RP VARIANT THR-572. RX PubMed=28449981; DOI=10.1016/j.pediatrneurol.2017.03.019; RA Eskandrani A., AlHashem A., Ali E.S., AlShahwan S., Tlili K., Hundallah K., RA Tabarki B.; RT "Recessive AFG3L2 Mutation Causes Progressive Microcephaly, Early Onset RT Seizures, Spasticity, and Basal Ganglia Involvement."; RL Pediatr. Neurol. 71:24-28(2017). RN [40] 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 [41] RP VARIANTS SCA28 CYS-616 AND MET-723. RX PubMed=31111429; DOI=10.1007/s12311-019-01036-2; RA Tunc S., Dulovic-Mahlow M., Baumann H., Baaske M.K., Jahn M., Junker J., RA Muenchau A., Brueggemann N., Lohmann K.; RT "Spinocerebellar ataxia type 28-phenotypic and molecular characterization RT of a family with heterozygous and compound-heterozygous mutations in RT AFG3L2."; RL Cerebellum 18:817-822(2019). RN [42] 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 [43] 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 [44] 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: Catalytic component of the m-AAA protease, a protease that CC plays a key role in proteostasis of inner mitochondrial membrane CC proteins, and which is essential for axonal and neuron development CC (PubMed:19748354, PubMed:28396416, PubMed:29932645, PubMed:30683687, CC PubMed:31327635, PubMed:37917749, PubMed:38157846). AFG3L2 possesses CC both ATPase and protease activities: the ATPase activity is required to CC unfold substrates, threading them into the internal proteolytic cavity CC for hydrolysis into small peptide fragments (PubMed:19748354, CC PubMed:31327635). The m-AAA protease carries out quality control in the CC inner membrane of the mitochondria by mediating degradation of CC mistranslated or misfolded polypeptides (PubMed:26504172, CC PubMed:30683687, PubMed:34718584). The m-AAA protease complex also CC promotes the processing and maturation of mitochondrial proteins, such CC as MRPL32/bL32m, PINK1 and SP7 (PubMed:22354088, PubMed:29932645, CC PubMed:30252181). Mediates protein maturation of the mitochondrial CC ribosomal subunit MRPL32/bL32m by catalyzing the cleavage of the CC presequence of MRPL32/bL32m prior to assembly into the mitochondrial CC ribosome (PubMed:29932645). Required for SPG7 maturation into its CC active mature form after SPG7 cleavage by mitochondrial-processing CC peptidase (MPP) (PubMed:30252181). Required for the maturation of PINK1 CC into its 52kDa mature form after its cleavage by mitochondrial- CC processing peptidase (MPP) (PubMed:22354088). Acts as a regulator of CC calcium in neurons by mediating degradation of SMDT1/EMRE before its CC assembly with the uniporter complex, limiting the availability of CC SMDT1/EMRE for MCU assembly and promoting efficient assembly of CC gatekeeper subunits with MCU (PubMed:27642048, PubMed:28396416). CC Promotes the proteolytic degradation of GHITM upon hyperpolarization of CC mitochondria: progressive GHITM degradation leads to respiratory CC complex I degradation and broad reshaping of the mitochondrial proteome CC by AFG3L2 (PubMed:35912435). Also acts as a regulator of mitochondrial CC glutathione homeostasis by mediating cleavage and degradation of CC SLC25A39 (PubMed:37917749, PubMed:38157846). SLC25A39 cleavage is CC prevented when SLC25A39 binds iron-sulfur (PubMed:37917749, CC PubMed:38157846). Involved in the regulation of OMA1-dependent CC processing of OPA1 (PubMed:17615298, PubMed:29545505, PubMed:30252181, CC PubMed:30683687, PubMed:32600459). May act by mediating processing of CC OMA1 precursor, participating in OMA1 maturation (PubMed:29545505). CC {ECO:0000269|PubMed:17615298, ECO:0000269|PubMed:19748354, CC ECO:0000269|PubMed:22354088, ECO:0000269|PubMed:26504172, CC ECO:0000269|PubMed:27642048, ECO:0000269|PubMed:28396416, CC ECO:0000269|PubMed:29545505, ECO:0000269|PubMed:29932645, CC ECO:0000269|PubMed:30252181, ECO:0000269|PubMed:30683687, CC ECO:0000269|PubMed:31327635, ECO:0000269|PubMed:32600459, CC ECO:0000269|PubMed:34718584, ECO:0000269|PubMed:35912435, CC ECO:0000269|PubMed:37917749, ECO:0000269|PubMed:38157846}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + H2O = ADP + phosphate + H(+); Xref=Rhea:RHEA:13065, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; CC Evidence={ECO:0000269|PubMed:19748354}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:13066; CC Evidence={ECO:0000269|PubMed:19748354}; CC -!- COFACTOR: CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105; CC Evidence={ECO:0000269|PubMed:31327635}; CC Note=Binds 1 zinc ion per subunit. {ECO:0000269|PubMed:31327635}; CC -!- SUBUNIT: Homohexamer (PubMed:24055473, PubMed:29932645, CC PubMed:31327635). Forms heterohexamers with SPG7 (PubMed:14623864, CC PubMed:17101804, PubMed:26387735, PubMed:28396416, PubMed:30252181). CC The m-AAA protease is either composed of homohexamers of AFG3L2 or CC heterohexamers of AFG3L2 and SPG7 (PubMed:17101804, PubMed:28396416). CC Interacts with MAIP1 (PubMed:27499296, PubMed:27642048). Interacts with CC DNAJC19 (By similarity). Interacts with PHB2 (By similarity). CC {ECO:0000250|UniProtKB:Q8JZQ2, ECO:0000269|PubMed:14623864, CC ECO:0000269|PubMed:17101804, ECO:0000269|PubMed:24055473, CC ECO:0000269|PubMed:26387735, ECO:0000269|PubMed:27499296, CC ECO:0000269|PubMed:27642048, ECO:0000269|PubMed:28396416, CC ECO:0000269|PubMed:29932645, ECO:0000269|PubMed:30252181, CC ECO:0000269|PubMed:31327635}. CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane CC {ECO:0000305|PubMed:10395799, ECO:0000305|PubMed:22354088, CC ECO:0000305|PubMed:31327635}; 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: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:24272953, ECO:0000269|PubMed:24293060, CC ECO:0000269|PubMed:24814845, ECO:0000269|PubMed:26454370, CC ECO:0000269|PubMed:26677414, ECO:0000269|PubMed:26868664, CC ECO:0000269|PubMed:28660440, ECO:0000269|PubMed:29053796, CC ECO:0000269|PubMed:30252181, ECO:0000269|PubMed:31111429, CC ECO:0000269|PubMed:31327635}. Note=The disease is caused by variants CC affecting the gene represented in this 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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; Y18314; CAB48398.1; -; mRNA. DR EMBL; BC065016; AAH65016.1; -; mRNA. DR CCDS; CCDS11859.1; -. DR RefSeq; NP_006787.2; NM_006796.3. 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 EMDB; EMD-0552; -. DR SMR; Q9Y4W6; -. DR BioGRID; 116139; 392. DR ComplexPortal; CPX-10318; m-AAA protease complex, AFG3L2 variant. DR ComplexPortal; CPX-10319; m-AAA protease complex, AFG3L2-SPG7 variant. DR CORUM; Q9Y4W6; -. DR FunCoup; Q9Y4W6; 2609. 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 jPOST; Q9Y4W6; -. DR MassIVE; Q9Y4W6; -. DR PaxDb; 9606-ENSP00000269143; -. DR PeptideAtlas; Q9Y4W6; -. DR ProteomicsDB; 86254; -. DR Pumba; Q9Y4W6; -. DR TopDownProteomics; Q9Y4W6; -. DR Antibodypedia; 1387; 265 antibodies from 31 providers. DR DNASU; 10939; -. DR Ensembl; ENST00000269143.8; ENSP00000269143.2; ENSG00000141385.13. 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 AGR; HGNC:315; -. DR ClinPGx; PA24612; -. DR CTD; 10939; -. DR DisGeNET; 10939; -. DR GeneCards; AFG3L2; -. DR GeneReviews; AFG3L2; -. DR HGNC; HGNC:315; AFG3L2. DR HPA; ENSG00000141385; Tissue enhanced (skeletal). DR MalaCards; AFG3L2; -. DR MIM; 604581; gene. DR MIM; 610246; phenotype. DR MIM; 614487; phenotype. DR MIM; 618977; phenotype. DR OpenTargets; ENSG00000141385; -. DR Orphanet; 313772; Early-onset spastic ataxia-myoclonic epilepsy-neuropathy syndrome. DR Orphanet; 101109; Spinocerebellar ataxia type 28. DR VEuPathDB; HostDB:ENSG00000141385; -. DR eggNOG; KOG0731; Eukaryota. DR GeneTree; ENSGT00940000159566; -. DR HOGENOM; CLU_000688_23_1_1; -. DR InParanoid; Q9Y4W6; -. DR OMA; ARQKGNF; -. DR OrthoDB; 1413014at2759; -. DR PAN-GO; Q9Y4W6; 3 GO annotations based on evolutionary models. DR PhylomeDB; Q9Y4W6; -. DR BRENDA; 3.4.24.B18; 2681. DR PathwayCommons; Q9Y4W6; -. DR Reactome; R-HSA-8949664; Processing of SMDT1. DR Reactome; R-HSA-9837999; Mitochondrial protein degradation. DR SignaLink; Q9Y4W6; -. DR Agora; ENSG00000141385; -. DR BioGRID-ORCS; 10939; 754 hits in 1181 CRISPR screens. DR CD-CODE; 91857CE7; Nucleolus. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; AFG3L2; human. DR EvolutionaryTrace; Q9Y4W6; -. 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 198 other cell types or tissues. DR ExpressionAtlas; Q9Y4W6; baseline and differential. DR GO; GO:0005745; C:m-AAA complex; IDA:UniProtKB. DR GO; GO:0005743; C:mitochondrial inner membrane; IDA:UniProt. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0033011; C:perinuclear theca; IDA:HPA. DR GO; GO:0120238; C:sperm glycocalyx; IDA:HPA. DR GO; GO:0120212; C:sperm head-tail coupling apparatus; IDA:HPA. DR GO; GO:0097225; C:sperm midpiece; IDA:HPA. DR GO; GO:0097228; C:sperm principal piece; IDA:HPA. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0016887; F:ATP hydrolysis activity; IDA:UniProtKB. 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:0072753; P:cellular response to glutathione; IDA: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:0141164; P:mitochondrial protein quality control; IDA:UniProtKB. 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:0030163; P:protein catabolic process; IDA:UniProtKB. DR GO; GO:0051604; P:protein maturation; IDA:UniProtKB. DR GO; GO:0016485; P:protein processing; ISS:UniProtKB. DR GO; GO:0006508; P:proteolysis; IDA:UniProtKB. DR GO; GO:0110097; P:regulation of calcium import into the mitochondrion; IDA:UniProtKB. DR GO; GO:0040014; P:regulation of multicellular organism growth; IEA:Ensembl. DR GO; GO:0060013; P:righting reflex; IEA:Ensembl. DR CDD; cd19501; RecA-like_FtsH; 1. DR FunFam; 1.10.8.60:FF:000019; AFG3-like AAA ATPase 2; 1. DR FunFam; 1.20.58.760:FF:000003; AFG3-like AAA ATPase 2; 1. DR FunFam; 3.40.1690.20:FF:000001; AFG3-like AAA ATPase 2; 1. DR FunFam; 3.40.50.300:FF:000001; ATP-dependent zinc metalloprotease FtsH; 1. DR Gene3D; 1.10.8.60; -; 1. DR Gene3D; 3.40.1690.20; -; 1. DR Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 1. DR Gene3D; 1.20.58.760; Peptidase M41; 1. DR HAMAP; MF_01458; FtsH; 1. DR InterPro; IPR003593; AAA+_ATPase. DR InterPro; IPR041569; AAA_lid_3. DR InterPro; IPR050928; ATP-dep_Zn_Metalloprotease. 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 NCBIfam; TIGR01241; FtsH_fam; 1. DR PANTHER; PTHR43655:SF9; AFG3-LIKE PROTEIN 2; 1. DR PANTHER; PTHR43655; ATP-DEPENDENT PROTEASE; 1. 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; FtsH protease domain-like; 1. DR SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 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; Proteomics identification; Reference proteome; KW Spinocerebellar ataxia; Transit peptide; Transmembrane; KW 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="Mitochondrial inner membrane m-AAA protease FT component AFG3L2" FT /id="PRO_0000442312" FT TOPO_DOM 39..142 FT /note="Mitochondrial matrix" FT /evidence="ECO:0000305|PubMed:31327635" FT TRANSMEM 143..163 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 164..250 FT /note="Mitochondrial intermembrane" FT /evidence="ECO:0000305|PubMed:31327635" FT TRANSMEM 251..271 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 272..797 FT /note="Mitochondrial matrix" FT /evidence="ECO:0000305|PubMed:31327635" 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 85..100 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 108..117 FT /note="Gly residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 775..797 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 575 FT /evidence="ECO:0000305|PubMed:31327635" FT BINDING 310 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000305|PubMed:31327635, FT ECO:0007744|PDB:6NYY" FT BINDING 311 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000305|PubMed:31327635, FT ECO:0007744|PDB:6NYY" FT BINDING 352 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000305|PubMed:31327635, FT ECO:0007744|PDB:6NYY" FT BINDING 353 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000305|PubMed:31327635, FT ECO:0007744|PDB:6NYY" FT BINDING 354 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000305|PubMed:31327635, FT ECO:0007744|PDB:6NYY" FT BINDING 355 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000305|PubMed:31327635, FT ECO:0007744|PDB:6NYY" FT BINDING 356 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000305|PubMed:31327635, FT ECO:0007744|PDB:6NYY" FT BINDING 490 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000305|PubMed:31327635, FT ECO:0007744|PDB:6NYY" FT BINDING 574 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:31327635, FT ECO:0007744|PDB:6NYY" FT BINDING 578 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:31327635, FT ECO:0007744|PDB:6NYY" FT BINDING 649 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:31327635, FT ECO:0007744|PDB:6NYY" FT MOD_RES 117 FT /note="N6-succinyllysine" FT /evidence="ECO:0000250|UniProtKB:Q8JZQ2" FT VARIANT 74 FT /note="E -> A (in OPA12; uncertain significance)" FT /evidence="ECO:0000269|PubMed:32548275" FT /id="VAR_084603" FT VARIANT 191 FT /note="V -> I (in SCA28; uncertain significance; FT dbSNP:rs1373473541)" FT /evidence="ECO:0000269|PubMed:26454370" FT /id="VAR_089087" FT VARIANT 306 FT /note="K -> E (in SPAX5; uncertain significance; FT dbSNP:rs1908569446)" 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; dbSNP:rs1908566777)" 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; uncertain significance; FT dbSNP:rs755893615)" FT /evidence="ECO:0000269|PubMed:32219868" FT /id="VAR_084607" FT VARIANT 376 FT /note="E -> K (in OPA12; uncertain significance)" FT /evidence="ECO:0000269|PubMed:32548275" FT /id="VAR_084608" FT VARIANT 377 FT /note="F -> S (in OPA12; uncertain significance; FT dbSNP:rs1908507433)" FT /evidence="ECO:0000269|PubMed:32219868" FT /id="VAR_084609" FT VARIANT 407 FT /note="D -> G (in OPA12; uncertain significance; decreased FT proteolytic function; dbSNP:rs1908371616)" FT /evidence="ECO:0000269|PubMed:32219868" FT /id="VAR_084610" FT VARIANT 416 FT /note="R -> S (in OPA12; uncertain significance)" FT /evidence="ECO:0000269|PubMed:32548275" FT /id="VAR_084611" FT VARIANT 430 FT /note="T -> I (in OPA12; uncertain significance; FT dbSNP:rs1908369114)" FT /evidence="ECO:0000269|PubMed:32219868" FT /id="VAR_084612" FT VARIANT 432 FT /note="N -> T (in SCA28; abolished ability to degrade FT substrate proteins; dbSNP:rs151344512)" FT /evidence="ECO:0000269|PubMed:20208537, FT ECO:0000269|PubMed:31327635" 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 dbSNP:rs1908309088)" 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 dbSNP:rs1908300748)" FT /evidence="ECO:0000269|PubMed:32219868, FT ECO:0000269|PubMed:32548275" FT /id="VAR_084616" FT VARIANT 572 FT /note="A -> T (found in patients from a consanguineous FT family with progressive microcephaly, early onset seizures, FT spasticity and basal ganglia involvement; uncertain FT significance; decreased ATPase and ability to degrade FT substrate proteins; dbSNP:rs562861748)" FT /evidence="ECO:0000269|PubMed:28449981, FT ECO:0000269|PubMed:31327635" FT /id="VAR_089088" FT VARIANT 605 FT /note="Y -> C (in OPA12; uncertain significance; FT dbSNP:rs773240455)" FT /evidence="ECO:0000269|PubMed:32219868" FT /id="VAR_084617" FT VARIANT 616 FT /note="Y -> C (in SPAX5 and SCA28; hypomorphic mutation; FT impaired oligomerization with itself and SPG7; increased FT ATPase and proteolytic activities; dbSNP:rs387906889)" FT /evidence="ECO:0000269|PubMed:22022284, FT ECO:0000269|PubMed:31111429, ECO:0000269|PubMed:31327635" FT /id="VAR_067330" FT VARIANT 620 FT /note="Q -> K (in SPAX5; impaired function shown in a yeast FT complementation assay; dbSNP:rs1907907851)" FT /evidence="ECO:0000269|PubMed:32219868" FT /id="VAR_084618" FT VARIANT 621 FT /note="L -> V (in SCA28; uncertain significance; FT dbSNP:rs756912142)" FT /evidence="ECO:0000269|PubMed:29053796" FT /id="VAR_080736" FT VARIANT 644 FT /note="T -> S (in OPA12; uncertain 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; abolished ability to degrade FT substrate proteins; dbSNP:rs151344515)" FT /evidence="ECO:0000269|PubMed:20725928, FT ECO:0000269|PubMed:31327635" 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 ECO:0000269|PubMed:28660440" FT /id="VAR_064407" FT VARIANT 688 FT /note="P -> T (in SCA28; uncertain significance; slightly FT decreased ability to degrade substrate proteins; FT dbSNP:rs797045221)" FT /evidence="ECO:0000269|PubMed:26868664, FT ECO:0000269|PubMed:31327635" FT /id="VAR_089089" 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; dbSNP:rs1598820860)" 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 VARIANT 723 FT /note="V -> M (in SCA28; dbSNP:rs139469785)" FT /evidence="ECO:0000269|PubMed:31111429" FT /id="VAR_089090" FT MUTAGEN 289 FT /note="F->A: Reduced rate of protein degradation." FT /evidence="ECO:0000269|PubMed:31327635" FT MUTAGEN 299 FT /note="L->A: Reduced rate of protein degradation." FT /evidence="ECO:0000269|PubMed:31327635" FT MUTAGEN 354 FT /note="K->A: Does not effect activity of the m-AAA protease FT complex." FT /evidence="ECO:0000269|PubMed:19748354" FT MUTAGEN 380 FT /note="M->K: Abolished ATPase and protease activities." FT /evidence="ECO:0000269|PubMed:31327635" FT MUTAGEN 380 FT /note="M->V: Increased ATP hydrolysis." FT /evidence="ECO:0000269|PubMed:31327635" FT MUTAGEN 408 FT /note="E->Q: Abolished ATPase activity, leading to impaired FT activity of the m-AAA protease complex, preventing cleavage FT and degradation of substrate proteins." FT /evidence="ECO:0000269|PubMed:19748354, FT ECO:0000269|PubMed:29932645, ECO:0000269|PubMed:37917749" FT MUTAGEN 421 FT /note="F->A: Impairted protease activity without affecting FT the ATPase activity." FT /evidence="ECO:0000269|PubMed:31327635" FT MUTAGEN 575 FT /note="E->Q: Abolished protease activity. Loss of FT autocatalytic processing. Impaired proteolytic maturation FT of SPG7." FT /evidence="ECO:0000269|PubMed:29932645, FT ECO:0000269|PubMed:30252181, ECO:0000269|PubMed:31327635" FT MUTAGEN 779 FT /note="W->R: Impaired ability to degrade substrates without FT affecting the ATPase activity." FT /evidence="ECO:0000269|PubMed:31327635" 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 //