MFN2_HUMAN
ID MFN2_HUMAN Reviewed; 757 AA.
AC O95140; A8K1B3; O95572; Q5JXC3; Q5JXC4; Q9H131; Q9NSX8;
DT 24-MAY-2004, integrated into UniProtKB/Swiss-Prot.
DT 24-MAY-2004, sequence version 3.
DT 03-AUG-2022, entry version 189.
DE RecName: Full=Mitofusin-2 {ECO:0000303|PubMed:12598526};
DE EC=3.6.5.- {ECO:0000269|PubMed:28114303};
DE AltName: Full=Transmembrane GTPase MFN2 {ECO:0000303|PubMed:28114303};
GN Name=MFN2 {ECO:0000303|PubMed:12598526, ECO:0000312|HGNC:HGNC:16877};
GN Synonyms=CPRP1, KIAA0214 {ECO:0000303|PubMed:9039502};
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] (ISOFORM 1).
RX PubMed=12598526; DOI=10.1074/jbc.m212754200;
RA Bach D., Pich S., Soriano F.X., Vega N., Baumgartner B., Oriola J.,
RA Daugaard J.R., Lloberas J., Camps M., Zierath J.R., Rabasa-Lhoret R.,
RA Wallberg-Henriksson H., Laville M., Palacin M., Vidal H., Rivera F.,
RA Brand M., Zorzano A.;
RT "Mitofusin-2 determines mitochondrial network architecture and
RT mitochondrial metabolism. A novel regulatory mechanism altered in
RT obesity.";
RL J. Biol. Chem. 278:17190-17197(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=15322553; DOI=10.1038/ncb1161;
RA Chen K.-H., Guo X., Ma D., Guo Y., Li Q., Yang D., Li P., Qiu X., Wen S.,
RA Xiao R.-P., Tang J.;
RT "Dysregulation of HSG triggers vascular proliferative disorders.";
RL Nat. Cell Biol. 6:872-883(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Bone marrow;
RX PubMed=9039502; DOI=10.1093/dnares/3.5.321;
RA Nagase T., Seki N., Ishikawa K., Ohira M., Kawarabayasi Y., Ohara O.,
RA Tanaka A., Kotani H., Miyajima N., Nomura N.;
RT "Prediction of the coding sequences of unidentified human genes. VI. The
RT coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of
RT cDNA clones from cell line KG-1 and brain.";
RL DNA Res. 3:321-329(1996).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Pancreas;
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 [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 553-757 (ISOFORM 1).
RC TISSUE=Testis;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [9]
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF LYS-109;
RP 622-GLY--VAL-624 AND 657-LYS--ARG-659.
RX PubMed=11181170; DOI=10.1242/jcs.114.5.867;
RA Santel A., Fuller M.T.;
RT "Control of mitochondrial morphology by a human mitofusin.";
RL J. Cell Sci. 114:867-874(2001).
RN [10]
RP FUNCTION, SUBCELLULAR LOCATION, MEMBRANE TOPOLOGY, TISSUE SPECIFICITY, AND
RP MUTAGENESIS OF LYS-109; SER-110 AND ARG-259.
RX PubMed=11950885; DOI=10.1242/jcs.115.8.1663;
RA Rojo M., Legros F., Chateau D., Lombes A.;
RT "Membrane topology and mitochondrial targeting of mitofusins, ubiquitous
RT mammalian homologs of the transmembrane GTPase Fzo.";
RL J. Cell Sci. 115:1663-1674(2002).
RN [11]
RP SUBCELLULAR LOCATION.
RX PubMed=12499352; DOI=10.1083/jcb.200209124;
RA Karbowski M., Lee Y.-J., Gaume B., Jeong S.-Y., Frank S., Nechushtan A.,
RA Santel A., Fuller M., Smith C.L., Youle R.J.;
RT "Spatial and temporal association of Bax with mitochondrial fission sites,
RT Drp1, and Mfn2 during apoptosis.";
RL J. Cell Biol. 159:931-938(2002).
RN [12]
RP TISSUE SPECIFICITY.
RX PubMed=12759376; DOI=10.1242/jcs.00479;
RA Santel A., Frank S., Gaume B., Herrler M., Youle R.J., Fuller M.T.;
RT "Mitofusin-1 protein is a generally expressed mediator of mitochondrial
RT fusion in mammalian cells.";
RL J. Cell Sci. 116:2763-2774(2003).
RN [13]
RP DISEASE, AND VARIANTS CMT2A2A PHE-69; PRO-76; GLN-94; ALA-251; HIS-280 AND
RP SER-740.
RX PubMed=15064763; DOI=10.1038/ng1341;
RA Zuechner S., Mersiyanova I.V., Muglia M., Bissar-Tadmouri N., Rochelle J.,
RA Dadali E.L., Zappia M., Nelis E., Patitucci A., Senderek J., Parman Y.,
RA Evgrafov O., Jonghe P.D., Takahashi Y., Tsuji S., Pericak-Vance M.A.,
RA Quattrone A., Battaloglu E., Polyakov A.V., Timmerman V., Schroeder J.M.,
RA Vance J.M.;
RT "Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-
RT Tooth neuropathy type 2A.";
RL Nat. Genet. 36:449-451(2004).
RN [14]
RP ERRATUM OF PUBMED:15064763.
RA Zuechner S., Mersiyanova I.V., Muglia M., Bissar-Tadmouri N., Rochelle J.,
RA Dadali E.L., Zappia M., Nelis E., Patitucci A., Senderek J., Parman Y.,
RA Evgrafov O., Jonghe P.D., Takahashi Y., Tsuji S., Pericak-Vance M.A.,
RA Quattrone A., Battaloglu E., Polyakov A.V., Timmerman V., Schroeder J.M.,
RA Vance J.M.;
RL Nat. Genet. 36:660-660(2004).
RN [15]
RP INTERACTION WITH STOML2.
RX PubMed=17121834; DOI=10.1074/jbc.m608168200;
RA Hajek P., Chomyn A., Attardi G.;
RT "Identification of a novel mitochondrial complex containing mitofusin 2 and
RT stomatin-like protein 2.";
RL J. Biol. Chem. 282:5670-5681(2007).
RN [16]
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 [17]
RP INVOLVEMENT IN CMT2A2B, AND VARIANTS CMT2A2B LYS-38 DEL; SER-216 AND
RP MET-362.
RX PubMed=21715711; DOI=10.1212/wnl.0b013e3182242d4d;
RA Polke J.M., Laura M., Pareyson D., Taroni F., Milani M., Bergamin G.,
RA Gibbons V.S., Hovdulden H., Chavdmley S.C., Blake J., Devile C.,
RA Sandford R., Sweeney M.G., Davis M.B., Reilly M.M.;
RT "Recessive axonal Charcot-Marie-Tooth disease due to compound heterozygous
RT mitofusin 2 mutations.";
RL Neurology 77:168-173(2011).
RN [18]
RP FUNCTION IN MITOPHAGY, INTERACTION WITH PRKN, PHOSPHORYLATION AT THR-111
RP AND SER-442 BY PINK1, UBIQUITINATION BY PRKN, SUBCELLULAR LOCATION, AND
RP MUTAGENESIS OF THR-111 AND SER-442.
RX PubMed=23620051; DOI=10.1126/science.1231031;
RA Chen Y., Dorn G.W. II;
RT "PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged
RT mitochondria.";
RL Science 340:471-475(2013).
RN [19]
RP INTERACTION WITH THG1L.
RX PubMed=25008184; DOI=10.2337/db13-1256;
RA Hickey F.B., Corcoran J.B., Griffin B., Bhreathnach U., Mortiboys H.,
RA Reid H.M., Andrews D., Byrne S., Furlong F., Martin F., Godson C.,
RA Murphy M.;
RT "IHG-1 increases mitochondrial fusion and bioenergetic function.";
RL Diabetes 63:4314-4325(2014).
RN [20]
RP FUNCTION, SUBUNIT, VARIANT CMT2A2B TRP-707, CHARACTERIZATION OF VARIANT
RP HMSN6A TRP-94, AND CHARACTERIZATION OF VARIANT CMT2A2B TRP-707.
RX PubMed=26085578; DOI=10.1093/hmg/ddv229;
RG Care4Rare Canada Consortium;
RA Sawyer S.L., Cheuk-Him Ng A., Innes A.M., Wagner J.D., Dyment D.A.,
RA Tetreault M., Majewski J., Boycott K.M., Screaton R.A., Nicholson G.;
RT "Homozygous mutations in MFN2 cause multiple symmetric lipomatosis
RT associated with neuropathy.";
RL Hum. Mol. Genet. 24:5109-5114(2015).
RN [21]
RP FUNCTION, UBIQUITINATION, AND SUBCELLULAR LOCATION.
RX PubMed=26214738; DOI=10.1038/nature14601;
RA Senyilmaz D., Virtue S., Xu X., Tan C.Y., Griffin J.L., Miller A.K.,
RA Vidal-Puig A., Teleman A.A.;
RT "Regulation of mitochondrial morphology and function by stearoylation of
RT TFR1.";
RL Nature 525:124-128(2015).
RN [22]
RP INVOLVEMENT IN CMT2A2B.
RX PubMed=26955893; DOI=10.1002/ajmg.a.37611;
RA Tan C.A., Rabideau M., Blevins A., Westbrook M.J., Ekstein T., Nykamp K.,
RA Deucher A., Harper A., Demmer L.;
RT "Autosomal recessive MFN2-related Charcot-Marie-Tooth disease with
RT diaphragmatic weakness: Case report and literature review.";
RL Am. J. Med. Genet. A 170:1580-1584(2016).
RN [23]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF HIS-128; GLU-230; ARG-259;
RP TRP-260 AND GLU-266.
RX PubMed=28114303; DOI=10.1038/nature21077;
RA Cao Y.L., Meng S., Chen Y., Feng J.X., Gu D.D., Yu B., Li Y.J., Yang J.Y.,
RA Liao S., Chan D.C., Gao S.;
RT "MFN1 structures reveal nucleotide-triggered dimerization critical for
RT mitochondrial fusion.";
RL Nature 542:372-376(2017).
RN [24]
RP UBIQUITINATION.
RX PubMed=30217973; DOI=10.1038/s41467-018-05722-3;
RA Di Rita A., Peschiaroli A., D'Acunzo P., Strobbe D., Hu Z., Gruber J.,
RA Nygaard M., Lambrughi M., Melino G., Papaleo E., Dengjel J., El Alaoui S.,
RA Campanella M., Doetsch V., Rogov V.V., Strappazzon F., Cecconi F.;
RT "HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating
RT AMBRA1 activation via IKKalpha.";
RL Nat. Commun. 9:3755-3755(2018).
RN [25]
RP VARIANT CMT2A2A ASN-357.
RX PubMed=15549395; DOI=10.1007/s00439-004-1199-2;
RA Kijima K., Numakura C., Izumino H., Umetsu K., Nezu A., Shiiki T.,
RA Ogawa M., Ishizaki Y., Kitamura T., Shozawa Y., Hayasaka K.;
RT "Mitochondrial GTPase mitofusin 2 mutation in Charcot-Marie-Tooth
RT neuropathy type 2A.";
RL Hum. Genet. 116:23-27(2005).
RN [26]
RP VARIANTS HMSN6A TRP-94; ILE-206; ARG-276; TYR-361 AND TRP-364.
RX PubMed=16437557; DOI=10.1002/ana.20797;
RA Zuechner S., De Jonghe P., Jordanova A., Claeys K.G., Guergueltcheva V.,
RA Cherninkova S., Hamilton S.R., Van Stavern G., Krajewski K.M., Stajich J.,
RA Tournev I., Verhoeven K., Langerhorst C.T., de Visser M., Baas F., Bird T.,
RA Timmerman V., Shy M., Vance J.M.;
RT "Axonal neuropathy with optic atrophy is caused by mutations in mitofusin
RT 2.";
RL Ann. Neurol. 59:276-281(2006).
RN [27]
RP VARIANTS CMT2A2A VAL-127; VAL-347; ILE-376 AND HIS-468, AND VARIANT
RP ILE-705.
RX PubMed=16762064; DOI=10.1186/1471-2350-7-53;
RA Engelfried K., Vorgerd M., Hagedorn M., Haas G., Gilles J., Epplen J.T.,
RA Meins M.;
RT "Charcot-Marie-Tooth neuropathy type 2A: novel mutations in the mitofusin 2
RT gene (MFN2).";
RL BMC Med. Genet. 7:53-53(2006).
RN [28]
RP VARIANTS CMT2A2B VAL-164; ASN-214; MET-362; ARG-390 AND TRP-707.
RX PubMed=18458227; DOI=10.1212/01.wnl.0000311275.89032.22;
RA Nicholson G.A., Magdelaine C., Zhu D., Grew S., Ryan M.M., Sturtz F.,
RA Vallat J.M., Ouvrier R.A.;
RT "Severe early-onset axonal neuropathy with homozygous and compound
RT heterozygous MFN2 mutations.";
RL Neurology 70:1678-1681(2008).
RN [29]
RP VARIANT HMSN6A TRP-94, VARIANT CMT2A2B GLN-94, VARIANTS HIS-468; SER-570;
RP ILE-705 AND THR-716, AND VARIANT CMT2A2A TRP-707.
RX PubMed=20350294; DOI=10.1186/1471-2350-11-48;
RA Braathen G.J., Sand J.C., Lobato A., Hoeyer H., Russell M.B.;
RT "MFN2 point mutations occur in 3.4% of Charcot-Marie-Tooth families. An
RT investigation of 232 Norwegian CMT families.";
RL BMC Med. Genet. 11:48-48(2010).
RN [30]
RP VARIANTS CMT2A2A VAL-233; TRP-364 AND MET-744.
RX PubMed=22206013; DOI=10.1371/journal.pone.0029393;
RA Lin K.P., Soong B.W., Yang C.C., Huang L.W., Chang M.H., Lee I.H.,
RA Antonellis A., Lee Y.C.;
RT "The mutational spectrum in a cohort of Charcot-Marie-Tooth disease type 2
RT among the Han Chinese in Taiwan.";
RL PLoS ONE 6:E29393-E29393(2011).
RN [31]
RP VARIANT ILE-705.
RX PubMed=26316991; DOI=10.1155/2013/495873;
RA Albulym O.M., Zhu D., Reddel S., Kennerson M., Nicholson G.;
RT "The MFN2 V705I variant is not a disease-causing mutation: a segregation
RT analysis in a CMT2 family.";
RL J. Neurodegener. Dis. 2013:495873-495873(2013).
RN [32]
RP VARIANT HIS-259.
RX PubMed=24627108; DOI=10.1007/s00415-014-7289-8;
RA Schabhuettl M., Wieland T., Senderek J., Baets J., Timmerman V.,
RA De Jonghe P., Reilly M.M., Stieglbauer K., Laich E., Windhager R., Erwa W.,
RA Trajanoski S., Strom T.M., Auer-Grumbach M.;
RT "Whole-exome sequencing in patients with inherited neuropathies: outcome
RT and challenges.";
RL J. Neurol. 261:970-982(2014).
RN [33]
RP VARIANT HMSN6A GLN-94.
RX PubMed=24604904; DOI=10.1136/jnnp-2013-306740;
RA Klein C.J., Middha S., Duan X., Wu Y., Litchy W.J., Gu W., Dyck P.J.,
RA Gavrilova R.H., Smith D.I., Kocher J.P., Dyck P.J.;
RT "Application of whole exome sequencing in undiagnosed inherited
RT polyneuropathies.";
RL J. Neurol. Neurosurg. Psych. 85:1265-1272(2014).
CC -!- FUNCTION: Mitochondrial outer membrane GTPase that mediates
CC mitochondrial clustering and fusion (PubMed:11181170, PubMed:11950885,
CC PubMed:26214738, PubMed:28114303). Mitochondria are highly dynamic
CC organelles, and their morphology is determined by the equilibrium
CC between mitochondrial fusion and fission events (PubMed:28114303).
CC Overexpression induces the formation of mitochondrial networks
CC (PubMed:28114303). Membrane clustering requires GTPase activity and may
CC involve a major rearrangement of the coiled coil domains (Probable).
CC Plays a central role in mitochondrial metabolism and may be associated
CC with obesity and/or apoptosis processes (By similarity). Plays an
CC important role in the regulation of vascular smooth muscle cell
CC proliferation (By similarity). Involved in the clearance of damaged
CC mitochondria via selective autophagy (mitophagy) (PubMed:23620051). Is
CC required for PRKN recruitment to dysfunctional mitochondria
CC (PubMed:23620051). Involved in the control of unfolded protein response
CC (UPR) upon ER stress including activation of apoptosis and autophagy
CC during ER stress (By similarity). Acts as an upstream regulator of
CC EIF2AK3 and suppresses EIF2AK3 activation under basal conditions (By
CC similarity). {ECO:0000250|UniProtKB:Q80U63,
CC ECO:0000250|UniProtKB:Q8R500, ECO:0000269|PubMed:11181170,
CC ECO:0000269|PubMed:11950885, ECO:0000269|PubMed:23620051,
CC ECO:0000269|PubMed:26085578, ECO:0000269|PubMed:26214738,
CC ECO:0000269|PubMed:28114303, ECO:0000305}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=GTP + H2O = GDP + H(+) + phosphate; Xref=Rhea:RHEA:19669,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:37565,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:58189;
CC Evidence={ECO:0000269|PubMed:28114303};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19670;
CC Evidence={ECO:0000269|PubMed:28114303};
CC -!- SUBUNIT: Forms homomultimers and heteromultimers with MFN1
CC (PubMed:26085578). Oligomerization is essential for mitochondrion
CC fusion (Probable). Interacts with VAT1 (By similarity). Interacts with
CC STOML2; may form heterooligomers (PubMed:17121834). Interacts
CC (phosphorylated) with PRKN (PubMed:23620051). Interacts with EIF2AK3
CC (By similarity). Interacts with THG1L; THG1L probably functions as a
CC guanyl-nucleotide exchange factor/GEF, activating MFN2.
CC {ECO:0000250|UniProtKB:Q80U63, ECO:0000250|UniProtKB:Q8R500,
CC ECO:0000269|PubMed:17121834, ECO:0000269|PubMed:23620051,
CC ECO:0000269|PubMed:25008184, ECO:0000269|PubMed:26085578, ECO:0000305}.
CC -!- INTERACTION:
CC O95140; Q5S007: LRRK2; NbExp=3; IntAct=EBI-3324756, EBI-5323863;
CC O95140; Q9NX47: MARCHF5; NbExp=2; IntAct=EBI-3324756, EBI-2341610;
CC O95140; Q8IWA4: MFN1; NbExp=2; IntAct=EBI-3324756, EBI-1048197;
CC O95140; O60260: PRKN; NbExp=4; IntAct=EBI-3324756, EBI-716346;
CC O95140; Q9Y512: SAMM50; NbExp=2; IntAct=EBI-3324756, EBI-748409;
CC -!- SUBCELLULAR LOCATION: Mitochondrion outer membrane
CC {ECO:0000269|PubMed:11181170, ECO:0000269|PubMed:11950885,
CC ECO:0000269|PubMed:12499352, ECO:0000269|PubMed:23620051,
CC ECO:0000269|PubMed:26214738}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:11181170, ECO:0000269|PubMed:11950885,
CC ECO:0000269|PubMed:12499352, ECO:0000269|PubMed:23620051}.
CC Note=Colocalizes with BAX during apoptosis.
CC {ECO:0000269|PubMed:12499352}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=O95140-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O95140-2; Sequence=VSP_015159, VSP_015160, VSP_015161;
CC -!- TISSUE SPECIFICITY: Ubiquitous; expressed at low level. Highly
CC expressed in heart and kidney. {ECO:0000269|PubMed:11950885,
CC ECO:0000269|PubMed:12759376}.
CC -!- DOMAIN: A helix bundle is formed by helices from the N-terminal and the
CC C-terminal part of the protein. The GTPase domain cannot be expressed
CC by itself, without the helix bundle. Rearrangement of the helix bundle
CC and/or of the coiled coil domains may bring membranes from adjacent
CC mitochondria into close contact, and thereby play a role in
CC mitochondrial fusion. {ECO:0000250|UniProtKB:Q8IWA4}.
CC -!- PTM: Phosphorylated by PINK1. {ECO:0000269|PubMed:23620051}.
CC -!- PTM: Ubiquitinated by non-degradative ubiquitin by PRKN, promoting
CC mitochondrial fusion; deubiquitination by USP30 inhibits mitochondrial
CC fusion (PubMed:23620051). Ubiquitinated by HUWE1 when dietary stearate
CC (C18:0) levels are low; ubiquitination inhibits mitochondrial fusion
CC (PubMed:26214738, PubMed:30217973). {ECO:0000269|PubMed:23620051,
CC ECO:0000269|PubMed:26214738, ECO:0000269|PubMed:30217973}.
CC -!- DISEASE: Charcot-Marie-Tooth disease 2A2B (CMT2A2B) [MIM:617087]: An
CC axonal form of Charcot-Marie-Tooth disease, a disorder of the
CC peripheral nervous system, characterized by progressive weakness and
CC atrophy, initially of the peroneal muscles and later of the distal
CC muscles of the arms. Charcot-Marie-Tooth disease is classified in two
CC main groups on the basis of electrophysiologic properties and
CC histopathology: primary peripheral demyelinating neuropathies
CC (designated CMT1 when they are dominantly inherited) and primary
CC peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group
CC are characterized by signs of axonal degeneration in the absence of
CC obvious myelin alterations, normal or slightly reduced nerve conduction
CC velocities, and progressive distal muscle weakness and atrophy. CMT2A2B
CC is a severe form with autosomal recessive inheritance.
CC {ECO:0000269|PubMed:18458227, ECO:0000269|PubMed:20350294,
CC ECO:0000269|PubMed:21715711, ECO:0000269|PubMed:26085578,
CC ECO:0000269|PubMed:26955893}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Charcot-Marie-Tooth disease 2A2A (CMT2A2A) [MIM:609260]: An
CC axonal form of Charcot-Marie-Tooth disease, a disorder of the
CC peripheral nervous system, characterized by progressive weakness and
CC atrophy, initially of the peroneal muscles and later of the distal
CC muscles of the arms. Charcot-Marie-Tooth disease is classified in two
CC main groups on the basis of electrophysiologic properties and
CC histopathology: primary peripheral demyelinating neuropathies
CC (designated CMT1 when they are dominantly inherited) and primary
CC peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group
CC are characterized by signs of axonal degeneration in the absence of
CC obvious myelin alterations, normal or slightly reduced nerve conduction
CC velocities, and progressive distal muscle weakness and atrophy.
CC {ECO:0000269|PubMed:15064763, ECO:0000269|PubMed:15549395,
CC ECO:0000269|PubMed:16762064, ECO:0000269|PubMed:20350294,
CC ECO:0000269|PubMed:22206013}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Neuropathy, hereditary motor and sensory, 6A, with optic
CC atrophy (HMSN6A) [MIM:601152]: An autosomal dominant neurologic
CC disorder characterized by optic atrophy and peripheral sensorimotor
CC neuropathy manifesting as axonal Charcot-Marie-Tooth disease. Charcot-
CC Marie-Tooth disease is a disorder of the peripheral nervous system,
CC characterized by progressive weakness and atrophy, initially of the
CC peroneal muscles and later of the distal muscles of the arms. It is
CC classified in two main groups on the basis of electrophysiologic
CC properties and histopathology: primary peripheral demyelinating
CC neuropathies and primary peripheral axonal neuropathies. Peripheral
CC axonal neuropathies are characterized by signs of axonal regeneration
CC in the absence of obvious myelin alterations, and normal or slightly
CC reduced nerve conduction velocities. {ECO:0000269|PubMed:16437557,
CC ECO:0000269|PubMed:20350294, ECO:0000269|PubMed:24604904,
CC ECO:0000269|PubMed:26085578}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the TRAFAC class dynamin-like GTPase
CC superfamily. Dynamin/Fzo/YdjA family. Mitofusin subfamily.
CC {ECO:0000255|PROSITE-ProRule:PRU01055}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA34389.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=CAB70866.2; Type=Frameshift; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=Inherited peripheral neuropathies mutation db;
CC URL="https://uantwerpen.vib.be/CMTMutations";
CC ---------------------------------------------------------------------------
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DR EMBL; AY028429; AAK18728.1; -; mRNA.
DR EMBL; AF036536; AAD02058.2; -; mRNA.
DR EMBL; D86987; BAA34389.2; ALT_INIT; mRNA.
DR EMBL; AK289828; BAF82517.1; -; mRNA.
DR EMBL; AL096840; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471130; EAW71726.1; -; Genomic_DNA.
DR EMBL; BC017061; AAH17061.1; -; mRNA.
DR EMBL; AL137666; CAB70866.2; ALT_FRAME; mRNA.
DR CCDS; CCDS30587.1; -. [O95140-1]
DR PIR; T46498; T46498.
DR RefSeq; NP_001121132.1; NM_001127660.1. [O95140-1]
DR RefSeq; NP_055689.1; NM_014874.3. [O95140-1]
DR RefSeq; XP_005263600.1; XM_005263543.3. [O95140-1]
DR RefSeq; XP_005263602.1; XM_005263545.3. [O95140-1]
DR RefSeq; XP_005263604.1; XM_005263547.3. [O95140-1]
DR RefSeq; XP_005263605.1; XM_005263548.3. [O95140-1]
DR PDB; 6JFK; X-ray; 2.00 A; A=73-419.
DR PDB; 6JFL; X-ray; 2.81 A; A/B/C/D=73-419.
DR PDB; 6JFM; X-ray; 2.09 A; A/B=381-419.
DR PDBsum; 6JFK; -.
DR PDBsum; 6JFL; -.
DR PDBsum; 6JFM; -.
DR AlphaFoldDB; O95140; -.
DR SMR; O95140; -.
DR BioGRID; 115255; 134.
DR DIP; DIP-42832N; -.
DR IntAct; O95140; 14.
DR MINT; O95140; -.
DR STRING; 9606.ENSP00000235329; -.
DR ChEMBL; CHEMBL4630807; -.
DR TCDB; 1.N.6.1.2; the mitochondrial inner/outer membrane fusion (mmf) family.
DR TCDB; 1.R.1.1.1; the membrane contact site (mcs) family.
DR iPTMnet; O95140; -.
DR PhosphoSitePlus; O95140; -.
DR SwissPalm; O95140; -.
DR BioMuta; MFN2; -.
DR EPD; O95140; -.
DR jPOST; O95140; -.
DR MassIVE; O95140; -.
DR MaxQB; O95140; -.
DR PaxDb; O95140; -.
DR PeptideAtlas; O95140; -.
DR PRIDE; O95140; -.
DR ProteomicsDB; 50659; -. [O95140-1]
DR ProteomicsDB; 50660; -. [O95140-2]
DR Antibodypedia; 28394; 762 antibodies from 45 providers.
DR DNASU; 9927; -.
DR Ensembl; ENST00000235329.10; ENSP00000235329.5; ENSG00000116688.18. [O95140-1]
DR Ensembl; ENST00000444836.5; ENSP00000416338.1; ENSG00000116688.18. [O95140-1]
DR Ensembl; ENST00000674548.1; ENSP00000502185.1; ENSG00000116688.18. [O95140-1]
DR Ensembl; ENST00000674817.1; ENSP00000502151.1; ENSG00000116688.18. [O95140-1]
DR Ensembl; ENST00000674910.1; ENSP00000501716.1; ENSG00000116688.18. [O95140-1]
DR Ensembl; ENST00000675053.1; ENSP00000501646.1; ENSG00000116688.18. [O95140-1]
DR Ensembl; ENST00000675113.1; ENSP00000502623.1; ENSG00000116688.18. [O95140-1]
DR Ensembl; ENST00000675231.1; ENSP00000502404.1; ENSG00000116688.18. [O95140-1]
DR Ensembl; ENST00000675919.1; ENSP00000501776.1; ENSG00000116688.18. [O95140-1]
DR Ensembl; ENST00000676293.1; ENSP00000502362.1; ENSG00000116688.18. [O95140-1]
DR GeneID; 9927; -.
DR KEGG; hsa:9927; -.
DR MANE-Select; ENST00000235329.10; ENSP00000235329.5; NM_014874.4; NP_055689.1.
DR UCSC; uc001atn.5; human. [O95140-1]
DR CTD; 9927; -.
DR DisGeNET; 9927; -.
DR GeneCards; MFN2; -.
DR GeneReviews; MFN2; -.
DR HGNC; HGNC:16877; MFN2.
DR HPA; ENSG00000116688; Tissue enhanced (heart muscle, skeletal muscle, tongue).
DR MalaCards; MFN2; -.
DR MIM; 601152; phenotype.
DR MIM; 608507; gene.
DR MIM; 609260; phenotype.
DR MIM; 617087; phenotype.
DR neXtProt; NX_O95140; -.
DR OpenTargets; ENSG00000116688; -.
DR Orphanet; 99947; Autosomal dominant Charcot-Marie-Tooth disease type 2A2.
DR Orphanet; 64751; Hereditary motor and sensory neuropathy type 5.
DR Orphanet; 90120; Hereditary motor and sensory neuropathy type 6.
DR Orphanet; 2398; Multiple symmetric lipomatosis.
DR Orphanet; 90118; Severe early-onset axonal neuropathy due to MFN2 deficiency.
DR PharmGKB; PA134986046; -.
DR VEuPathDB; HostDB:ENSG00000116688; -.
DR eggNOG; KOG0448; Eukaryota.
DR GeneTree; ENSGT00390000013727; -.
DR HOGENOM; CLU_021212_2_0_1; -.
DR InParanoid; O95140; -.
DR OMA; LEFRFSF; -.
DR OrthoDB; 216494at2759; -.
DR PhylomeDB; O95140; -.
DR TreeFam; TF314289; -.
DR PathwayCommons; O95140; -.
DR Reactome; R-HSA-5205685; PINK1-PRKN Mediated Mitophagy.
DR Reactome; R-HSA-9013419; RHOT2 GTPase cycle.
DR Reactome; R-HSA-983231; Factors involved in megakaryocyte development and platelet production.
DR SignaLink; O95140; -.
DR SIGNOR; O95140; -.
DR BioGRID-ORCS; 9927; 564 hits in 1087 CRISPR screens.
DR ChiTaRS; MFN2; human.
DR GeneWiki; MFN2; -.
DR GenomeRNAi; 9927; -.
DR Pharos; O95140; Tbio.
DR PRO; PR:O95140; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; O95140; protein.
DR Bgee; ENSG00000116688; Expressed in apex of heart and 212 other tissues.
DR ExpressionAtlas; O95140; baseline and differential.
DR Genevisible; O95140; HS.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0031306; C:intrinsic component of mitochondrial outer membrane; ISS:UniProtKB.
DR GO; GO:0015630; C:microtubule cytoskeleton; IEA:Ensembl.
DR GO; GO:0005741; C:mitochondrial outer membrane; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW.
DR GO; GO:0003924; F:GTPase activity; IBA:GO_Central.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0001825; P:blastocyst formation; IEA:Ensembl.
DR GO; GO:0048593; P:camera-type eye morphogenesis; IEA:Ensembl.
DR GO; GO:0008053; P:mitochondrial fusion; IMP:UniProtKB.
DR GO; GO:0007006; P:mitochondrial membrane organization; IDA:UniProtKB.
DR GO; GO:0051646; P:mitochondrion localization; IDA:UniProtKB.
DR GO; GO:0046580; P:negative regulation of Ras protein signal transduction; IDA:UniProtKB.
DR GO; GO:0048662; P:negative regulation of smooth muscle cell proliferation; ISS:UniProtKB.
DR GO; GO:0061734; P:parkin-mediated stimulation of mitophagy in response to mitochondrial depolarization; ISS:ParkinsonsUK-UCL.
DR GO; GO:0120162; P:positive regulation of cold-induced thermogenesis; ISS:YuBioLab.
DR GO; GO:1905461; P:positive regulation of vascular associated smooth muscle cell apoptotic process; IMP:BHF-UCL.
DR GO; GO:1904707; P:positive regulation of vascular associated smooth muscle cell proliferation; IMP:BHF-UCL.
DR GO; GO:0034497; P:protein localization to phagophore assembly site; IDA:MGI.
DR GO; GO:0006626; P:protein targeting to mitochondrion; IDA:UniProtKB.
DR GO; GO:0006986; P:response to unfolded protein; IEA:UniProtKB-KW.
DR Gene3D; 3.40.50.300; -; 1.
DR InterPro; IPR045063; Dynamin_N.
DR InterPro; IPR006884; Fzo/mitofusin_HR2.
DR InterPro; IPR030381; G_DYNAMIN_dom.
DR InterPro; IPR027089; Mitofusin-2.
DR InterPro; IPR027094; Mitofusin_fam.
DR InterPro; IPR027417; P-loop_NTPase.
DR PANTHER; PTHR10465; PTHR10465; 1.
DR PANTHER; PTHR10465:SF1; PTHR10465:SF1; 1.
DR Pfam; PF00350; Dynamin_N; 1.
DR Pfam; PF04799; Fzo_mitofusin; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR PROSITE; PS51718; G_DYNAMIN_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Apoptosis; Autophagy;
KW Charcot-Marie-Tooth disease; Coiled coil; Disease variant; GTP-binding;
KW Hydrolase; Membrane; Mitochondrion; Mitochondrion outer membrane;
KW Neurodegeneration; Neuropathy; Nucleotide-binding; Phosphoprotein;
KW Reference proteome; Transmembrane; Transmembrane helix; Ubl conjugation;
KW Unfolded protein response.
FT CHAIN 1..757
FT /note="Mitofusin-2"
FT /id="PRO_0000127675"
FT TOPO_DOM 1..604
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 605..625
FT /note="Helical; Name=1"
FT /evidence="ECO:0000255"
FT TOPO_DOM 626
FT /note="Mitochondrial intermembrane"
FT /evidence="ECO:0000255"
FT TRANSMEM 627..647
FT /note="Helical; Name=2"
FT /evidence="ECO:0000255"
FT TOPO_DOM 648..757
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 93..342
FT /note="Dynamin-type G"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01055"
FT REGION 30..94
FT /note="Part of a helix bundle domain, formed by helices
FT from N-terminal and C-terminal regions"
FT /evidence="ECO:0000250|UniProtKB:Q8IWA4"
FT REGION 103..110
FT /note="G1 motif"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01055"
FT REGION 129..130
FT /note="G2 motif"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01055"
FT REGION 199..202
FT /note="G3 motif"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01055"
FT REGION 258..261
FT /note="G4 motif"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01055"
FT REGION 288
FT /note="G5 motif"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01055"
FT REGION 359..385
FT /note="Part of a helix bundle domain, formed by helices
FT from N-terminal and C-terminal regions"
FT /evidence="ECO:0000250|UniProtKB:Q8IWA4"
FT REGION 722..753
FT /note="Part of a helix bundle domain, formed by helices
FT from N-terminal and C-terminal regions"
FT /evidence="ECO:0000250|UniProtKB:Q8IWA4"
FT COILED 391..434
FT /evidence="ECO:0000255"
FT COILED 695..738
FT /evidence="ECO:0000255"
FT BINDING 106..111
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000250|UniProtKB:Q8IWA4"
FT BINDING 258..261
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000250|UniProtKB:Q8IWA4"
FT BINDING 305
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000250|UniProtKB:Q8IWA4"
FT BINDING 307
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000250|UniProtKB:Q8IWA4"
FT MOD_RES 111
FT /note="Phosphothreonine; by PINK1"
FT /evidence="ECO:0000305|PubMed:23620051"
FT MOD_RES 442
FT /note="Phosphoserine; by PINK1"
FT /evidence="ECO:0000305|PubMed:23620051"
FT VAR_SEQ 1..302
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_015159"
FT VAR_SEQ 303..324
FT /note="FVSAKEVLNARIQKAQGMPEGG -> MHPHLSTLSLPRRRSMAFLSSW (in
FT isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_015160"
FT VAR_SEQ 705..757
FT /note="VTRENLEQEIAAMNKKIEVLDSLQSKAKLLRNKAGWLDSELNMFTHQYLQPS
FT R -> GETLSERSMAKSTLMLLTLLFLCSFAGAQDVLTQ (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_015161"
FT VARIANT 38
FT /note="Missing (in CMT2A2B)"
FT /evidence="ECO:0000269|PubMed:21715711"
FT /id="VAR_076895"
FT VARIANT 69
FT /note="V -> F (in CMT2A2A; dbSNP:rs28940296)"
FT /evidence="ECO:0000269|PubMed:15064763"
FT /id="VAR_018607"
FT VARIANT 76
FT /note="L -> P (in CMT2A2A; dbSNP:rs28940293)"
FT /evidence="ECO:0000269|PubMed:15064763"
FT /id="VAR_018608"
FT VARIANT 94
FT /note="R -> Q (in CMT2A2A, CMT2A2B and HMSN6A;
FT dbSNP:rs28940291)"
FT /evidence="ECO:0000269|PubMed:15064763,
FT ECO:0000269|PubMed:20350294, ECO:0000269|PubMed:24604904"
FT /id="VAR_018609"
FT VARIANT 94
FT /note="R -> W (in HMSN6A; severely reduced homo-
FT oligomerization; no effect on hetero-oligomerization with
FT MFN1; dbSNP:rs119103263)"
FT /evidence="ECO:0000269|PubMed:16437557,
FT ECO:0000269|PubMed:20350294, ECO:0000269|PubMed:26085578"
FT /id="VAR_029876"
FT VARIANT 127
FT /note="G -> V (in CMT2A2A; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:16762064"
FT /id="VAR_078437"
FT VARIANT 164
FT /note="A -> V (in CMT2A2B; unknown pathological
FT significance; dbSNP:rs1553142699)"
FT /evidence="ECO:0000269|PubMed:18458227"
FT /id="VAR_080339"
FT VARIANT 206
FT /note="T -> I (in HMSN6A; dbSNP:rs119103266)"
FT /evidence="ECO:0000269|PubMed:16437557"
FT /id="VAR_029877"
FT VARIANT 214
FT /note="D -> N (in CMT2A2B; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:18458227"
FT /id="VAR_080340"
FT VARIANT 216
FT /note="F -> S (in CMT2A2B; dbSNP:rs387906990)"
FT /evidence="ECO:0000269|PubMed:21715711"
FT /id="VAR_076896"
FT VARIANT 233
FT /note="L -> V (in CMT2A2A)"
FT /evidence="ECO:0000269|PubMed:22206013"
FT /id="VAR_067088"
FT VARIANT 251
FT /note="P -> A (in CMT2A2A; dbSNP:rs28940295)"
FT /evidence="ECO:0000269|PubMed:15064763"
FT /id="VAR_018610"
FT VARIANT 259
FT /note="R -> H (found in a patient with hereditary motor and
FT sensory neuropathy; unknown pathological significance;
FT dbSNP:rs755065651)"
FT /evidence="ECO:0000269|PubMed:24627108"
FT /id="VAR_073291"
FT VARIANT 276
FT /note="Q -> R (in HMSN6A; dbSNP:rs119103264)"
FT /evidence="ECO:0000269|PubMed:16437557"
FT /id="VAR_029878"
FT VARIANT 280
FT /note="R -> H (in CMT2A2A; dbSNP:rs28940294)"
FT /evidence="ECO:0000269|PubMed:15064763"
FT /id="VAR_018611"
FT VARIANT 347
FT /note="E -> V (in CMT2A2A; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:16762064"
FT /id="VAR_078438"
FT VARIANT 357
FT /note="K -> N (in CMT2A2A; dbSNP:rs119103261)"
FT /evidence="ECO:0000269|PubMed:15549395"
FT /id="VAR_022464"
FT VARIANT 361
FT /note="H -> Y (in HMSN6A)"
FT /evidence="ECO:0000269|PubMed:16437557"
FT /id="VAR_029879"
FT VARIANT 362
FT /note="T -> M (in CMT2A2B; unknown pathological
FT significance; dbSNP:rs387906991)"
FT /evidence="ECO:0000269|PubMed:18458227,
FT ECO:0000269|PubMed:21715711"
FT /id="VAR_076897"
FT VARIANT 364
FT /note="R -> W (in HMSN6A and CMT2A2A; dbSNP:rs119103265)"
FT /evidence="ECO:0000269|PubMed:16437557,
FT ECO:0000269|PubMed:22206013"
FT /id="VAR_029880"
FT VARIANT 376
FT /note="M -> I (in CMT2A2A; unknown pathological
FT significance; dbSNP:rs1553144059)"
FT /evidence="ECO:0000269|PubMed:16762064"
FT /id="VAR_078439"
FT VARIANT 390
FT /note="C -> R (in CMT2A2B; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:18458227"
FT /id="VAR_080341"
FT VARIANT 468
FT /note="R -> H (in CMT2A2A; also found in patients with an
FT unclassified form of Charcot-Marie-Tooth disease; unknown
FT pathological significance; dbSNP:rs138382758)"
FT /evidence="ECO:0000269|PubMed:16762064,
FT ECO:0000269|PubMed:20350294"
FT /id="VAR_078440"
FT VARIANT 570
FT /note="N -> S (found in a patient with hereditary motor
FT neuropathy; unknown pathological significance;
FT dbSNP:rs376925978)"
FT /evidence="ECO:0000269|PubMed:20350294"
FT /id="VAR_078441"
FT VARIANT 705
FT /note="V -> I (in dbSNP:rs142271930)"
FT /evidence="ECO:0000269|PubMed:16762064,
FT ECO:0000269|PubMed:20350294, ECO:0000269|PubMed:26316991"
FT /id="VAR_078442"
FT VARIANT 707
FT /note="R -> W (in CMT2A2A and CMT2A2B; decreased function
FT in mitochondrial fusion; reduced homo-oligomerization; no
FT effect on hetero-oligomerization with MFN1;
FT dbSNP:rs119103267)"
FT /evidence="ECO:0000269|PubMed:18458227,
FT ECO:0000269|PubMed:20350294, ECO:0000269|PubMed:26085578"
FT /id="VAR_078443"
FT VARIANT 716
FT /note="A -> T (found in a patient with intermediate
FT Charcot-Marie-Tooth disease; unknown pathological
FT significance; dbSNP:rs144860227)"
FT /evidence="ECO:0000269|PubMed:20350294"
FT /id="VAR_078444"
FT VARIANT 740
FT /note="W -> S (in CMT2A2A; dbSNP:rs28940292)"
FT /evidence="ECO:0000269|PubMed:15064763"
FT /id="VAR_018612"
FT VARIANT 744
FT /note="E -> M (in CMT2A2A; requires 2 nucleotide
FT substitutions)"
FT /evidence="ECO:0000269|PubMed:22206013"
FT /id="VAR_067089"
FT MUTAGEN 109
FT /note="K->A,T: Does not affect its ability to cluster
FT mitochondria; when overexpressed."
FT /evidence="ECO:0000269|PubMed:11181170,
FT ECO:0000269|PubMed:11950885"
FT MUTAGEN 110
FT /note="S->N: Does not affect its ability to cluster
FT mitochondria; when overexpressed."
FT /evidence="ECO:0000269|PubMed:11950885"
FT MUTAGEN 111
FT /note="T->A: Diminishes interaction with PRKN in presence
FT of PINK1. Abolishes phosphorylation by PINK1 and
FT interaction with PRKN in presence of PINK1; when associated
FT with ALA-442."
FT /evidence="ECO:0000269|PubMed:23620051"
FT MUTAGEN 111
FT /note="T->E: Interacts with PRKN in absence of PINK1; when
FT associated with GLU-442."
FT /evidence="ECO:0000269|PubMed:23620051"
FT MUTAGEN 128
FT /note="H->A: Loss of function in promoting mitochondrial
FT fusion."
FT /evidence="ECO:0000269|PubMed:28114303"
FT MUTAGEN 230
FT /note="E->A: Loss of function in promoting mitochondrial
FT fusion."
FT /evidence="ECO:0000269|PubMed:28114303"
FT MUTAGEN 259
FT /note="R->A: Loss of function in promoting mitochondrial
FT fusion."
FT /evidence="ECO:0000269|PubMed:28114303"
FT MUTAGEN 259
FT /note="R->L: Does not affect its ability to cluster
FT mitochondria; when overexpressed."
FT /evidence="ECO:0000269|PubMed:11950885"
FT MUTAGEN 260
FT /note="W->A: Loss of function in promoting mitochondrial
FT fusion."
FT /evidence="ECO:0000269|PubMed:28114303"
FT MUTAGEN 266
FT /note="E->A: Loss of function in promoting mitochondrial
FT fusion."
FT /evidence="ECO:0000269|PubMed:28114303"
FT MUTAGEN 442
FT /note="S->A: Diminishes interaction with PRKN in presence
FT of PINK1. Abolishes phosphorylation by PINK1 and
FT interaction with PRKN in presence of PINK1; when associated
FT with ALA-111."
FT /evidence="ECO:0000269|PubMed:23620051"
FT MUTAGEN 442
FT /note="S->E: Interacts with PRKN in absence of PINK1; when
FT associated with GLU-111."
FT /evidence="ECO:0000269|PubMed:23620051"
FT MUTAGEN 622..624
FT /note="GGV->AAL: Does not affect the targeting to
FT mitochondrial outer membrane."
FT /evidence="ECO:0000269|PubMed:11181170"
FT MUTAGEN 622..624
FT /note="GGV->RRE: Abolishes the targeting to mitochondrial
FT outer membrane."
FT /evidence="ECO:0000269|PubMed:11181170"
FT MUTAGEN 657..659
FT /note="KER->TGV: Does not affect the targeting to
FT mitochondrial outer membrane."
FT /evidence="ECO:0000269|PubMed:11181170"
FT CONFLICT 521
FT /note="C -> P (in Ref. 2; AAD02058)"
FT /evidence="ECO:0000305"
FT HELIX 29..62
FT /evidence="ECO:0007829|PDB:6JFK"
FT HELIX 72..92
FT /evidence="ECO:0007829|PDB:6JFK"
FT STRAND 97..102
FT /evidence="ECO:0007829|PDB:6JFK"
FT HELIX 105..107
FT /evidence="ECO:0007829|PDB:6JFM"
FT HELIX 109..116
FT /evidence="ECO:0007829|PDB:6JFK"
FT STRAND 132..143
FT /evidence="ECO:0007829|PDB:6JFK"
FT STRAND 145..148
FT /evidence="ECO:0007829|PDB:6JFK"
FT TURN 149..151
FT /evidence="ECO:0007829|PDB:6JFK"
FT STRAND 154..156
FT /evidence="ECO:0007829|PDB:6JFK"
FT HELIX 160..168
FT /evidence="ECO:0007829|PDB:6JFK"
FT STRAND 178..184
FT /evidence="ECO:0007829|PDB:6JFK"
FT HELIX 185..187
FT /evidence="ECO:0007829|PDB:6JFK"
FT HELIX 189..192
FT /evidence="ECO:0007829|PDB:6JFK"
FT STRAND 195..199
FT /evidence="ECO:0007829|PDB:6JFK"
FT HELIX 209..216
FT /evidence="ECO:0007829|PDB:6JFK"
FT TURN 217..219
FT /evidence="ECO:0007829|PDB:6JFK"
FT STRAND 221..228
FT /evidence="ECO:0007829|PDB:6JFK"
FT HELIX 235..247
FT /evidence="ECO:0007829|PDB:6JFK"
FT STRAND 248..250
FT /evidence="ECO:0007829|PDB:6JFK"
FT STRAND 252..258
FT /evidence="ECO:0007829|PDB:6JFK"
FT HELIX 260..265
FT /evidence="ECO:0007829|PDB:6JFK"
FT TURN 267..269
FT /evidence="ECO:0007829|PDB:6JFK"
FT HELIX 270..287
FT /evidence="ECO:0007829|PDB:6JFK"
FT HELIX 294..299
FT /evidence="ECO:0007829|PDB:6JFK"
FT STRAND 301..303
FT /evidence="ECO:0007829|PDB:6JFK"
FT HELIX 306..317
FT /evidence="ECO:0007829|PDB:6JFK"
FT HELIX 322..325
FT /evidence="ECO:0007829|PDB:6JFK"
FT HELIX 331..397
FT /evidence="ECO:0007829|PDB:6JFK"
FT TURN 398..400
FT /evidence="ECO:0007829|PDB:6JFK"
FT HELIX 409..419
FT /evidence="ECO:0007829|PDB:6JFK"
SQ SEQUENCE 757 AA; 86402 MW; 6F859D740152DFAD CRC64;
MSLLFSRCNS IVTVKKNKRH MAEVNASPLK HFVTAKKKIN GIFEQLGAYI QESATFLEDT
YRNAELDPVT TEEQVLDVKG YLSKVRGISE VLARRHMKVA FFGRTSNGKS TVINAMLWDK
VLPSGIGHTT NCFLRVEGTD GHEAFLLTEG SEEKRSAKTV NQLAHALHQD KQLHAGSLVS
VMWPNSKCPL LKDDLVLMDS PGIDVTTELD SWIDKFCLDA DVFVLVANSE STLMQTEKHF
FHKVSERLSR PNIFILNNRW DASASEPEYM EEVRRQHMER CTSFLVDELG VVDRSQAGDR
IFFVSAKEVL NARIQKAQGM PEGGGALAEG FQVRMFEFQN FERRFEECIS QSAVKTKFEQ
HTVRAKQIAE AVRLIMDSLH MAAREQQVYC EEMREERQDR LKFIDKQLEL LAQDYKLRIK
QITEEVERQV STAMAEEIRR LSVLVDDYQM DFHPSPVVLK VYKNELHRHI EEGLGRNMSD
RCSTAITNSL QTMQQDMIDG LKPLLPVSVR SQIDMLVPRQ CFSLNYDLNC DKLCADFQED
IEFHFSLGWT MLVNRFLGPK NSRRALMGYN DQVQRPIPLT PANPSMPPLP QGSLTQEEFM
VSMVTGLASL TSRTSMGILV VGGVVWKAVG WRLIALSFGL YGLLYVYERL TWTTKAKERA
FKRQFVEHAS EKLQLVISYT GSNCSHQVQQ ELSGTFAHLC QQVDVTRENL EQEIAAMNKK
IEVLDSLQSK AKLLRNKAGW LDSELNMFTH QYLQPSR
