MFN2_RAT
ID MFN2_RAT Reviewed; 757 AA.
AC Q8R500; O09013;
DT 24-MAY-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2002, sequence version 1.
DT 03-AUG-2022, entry version 124.
DE RecName: Full=Mitofusin-2;
DE EC=3.6.5.- {ECO:0000250|UniProtKB:O95140};
DE AltName: Full=Mitochondrial transmembrane GTPase FZO1A;
DE Short=Protein HSG;
DE AltName: Full=Transmembrane GTPase MFN2;
GN Name=Mfn2; Synonyms=Fzo1a;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, TISSUE
RP SPECIFICITY, MULTIMERIZATION, SUBUNIT, AND MUTAGENESIS OF LYS-109.
RC TISSUE=Liver;
RX PubMed=14561718; DOI=10.1093/jb/mvg150;
RA Eura Y., Ishihara N., Yokota S., Mihara K.;
RT "Two mitofusin proteins, mammalian homologues of FZO, with distinct
RT functions are both required for mitochondrial fusion.";
RL J. Biochem. 134:333-344(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, AND TISSUE
RP SPECIFICITY.
RC STRAIN=SHR, and Wistar Kyoto; TISSUE=Aorta;
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 FUNCTION.
RX PubMed=12589796; DOI=10.1016/s0006-291x(03)00050-0;
RA Ishihara N., Jofuku A., Eura Y., Mihara K.;
RT "Regulation of mitochondrial morphology by membrane potential, and DRP1-
RT dependent division and FZO1-dependent fusion reaction in mammalian cells.";
RL Biochem. Biophys. Res. Commun. 301:891-898(2003).
RN [4]
RP TISSUE SPECIFICITY.
RX PubMed=14592431; DOI=10.1016/j.bbrc.2003.10.008;
RA Honda S., Hirose S.;
RT "Stage-specific enhanced expression of mitochondrial fusion and fission
RT factors during spermatogenesis in rat testis.";
RL Biochem. Biophys. Res. Commun. 311:424-432(2003).
RN [5]
RP FUNCTION.
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 [6]
RP INTERACTION WITH VAT1.
RX PubMed=17105775; DOI=10.1242/jcs.03253;
RA Eura Y., Ishihara N., Oka T., Mihara K.;
RT "Identification of a novel protein that regulates mitochondrial fusion by
RT modulating mitofusin (Mfn) protein function.";
RL J. Cell Sci. 119:4913-4925(2006).
CC -!- FUNCTION: Mitochondrial outer membrane GTPase that mediates
CC mitochondrial clustering and fusion (PubMed:14561718, PubMed:15322553,
CC PubMed:12589796, PubMed:12598526). Mitochondria are highly dynamic
CC organelles, and their morphology is determined by the equilibrium
CC between mitochondrial fusion and fission events. Overexpression induces
CC the formation of mitochondrial networks. Membrane clustering requires
CC GTPase activity and may involve a major rearrangement of the coiled
CC coil domains (By similarity). Plays a central role in mitochondrial
CC metabolism and may be associated with obesity and/or apoptosis
CC processes (PubMed:12598526). Plays an important role in the regulation
CC of vascular smooth muscle cell proliferation (PubMed:15322553).
CC Involved in the clearance of damaged mitochondria via selective
CC autophagy (mitophagy). Is required for PRKN recruitment to
CC dysfunctional mitochondria (By similarity). Involved in the control of
CC unfolded protein response (UPR) upon ER stress including activation of
CC apoptosis and autophagy during ER stress (By similarity). Acts as an
CC upstream regulator of EIF2AK3 and suppresses EIF2AK3 activation under
CC basal conditions (By similarity). {ECO:0000250|UniProtKB:O95140,
CC ECO:0000250|UniProtKB:Q80U63, ECO:0000269|PubMed:12589796,
CC ECO:0000269|PubMed:12598526, ECO:0000269|PubMed:14561718,
CC ECO:0000269|PubMed:15322553}.
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:0000250|UniProtKB:O95140};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19670;
CC Evidence={ECO:0000250|UniProtKB:O95140};
CC -!- SUBUNIT: Forms homomultimers and heteromultimers with MFN1
CC (PubMed:14561718). Oligomerization is essential for mitochondrion
CC fusion (Probable). Interacts with VAT1 (PubMed:17105775). Interacts
CC with STOML2; may form heterooligomers (By similarity). Interacts
CC (phosphorylated) with PRKN (By similarity). Interacts with EIF2AK3 (By
CC similarity). Interacts with THG1L; THG1L probably functions as a
CC guanyl-nucleotide exchange factor/GEF, activating MFN2.
CC {ECO:0000250|UniProtKB:O95140, ECO:0000250|UniProtKB:Q80U63,
CC ECO:0000269|PubMed:14561718, ECO:0000269|PubMed:17105775, ECO:0000305}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion outer membrane
CC {ECO:0000269|PubMed:14561718, ECO:0000269|PubMed:15322553}; Multi-pass
CC membrane protein {ECO:0000269|PubMed:14561718}. Note=Colocalizes with
CC BAX during apoptosis. {ECO:0000250|UniProtKB:O95140}.
CC -!- TISSUE SPECIFICITY: Ubiquitous. In brain, it is more expressed than
CC MFN1, while it is expressed at a weaker level than MFN1 in heart and
CC testis. Expressed at high level in elongating spermatids of
CC seminiferous tubules. Expression is markedly down-regulated in highly
CC proliferative vascular smooth muscle cells (VSMCs) from the genetic
CC hypertensive animal model SHR, as well as in balloon-injured Wistar
CC Kyoto arteries. {ECO:0000269|PubMed:14561718,
CC ECO:0000269|PubMed:14592431, ECO:0000269|PubMed:15322553}.
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:0000250|UniProtKB:O95140}.
CC -!- PTM: Ubiquitinated by non-degradative ubiquitin by PRKN, promoting
CC mitochondrial fusion; deubiquitination by USP30 inhibits mitochondrial
CC fusion (By similarity). Ubiquitinated by HUWE1 when dietary stearate
CC (C18:0) levels are low; ubiquitination inhibits mitochondrial fusion
CC (By similarity). {ECO:0000250|UniProtKB:O95140}.
CC -!- SIMILARITY: Belongs to the TRAFAC class dynamin-like GTPase
CC superfamily. Dynamin/Fzo/YdjA family. Mitofusin subfamily.
CC {ECO:0000255|PROSITE-ProRule:PRU01055}.
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DR EMBL; AB084165; BAB90982.1; -; mRNA.
DR EMBL; U41803; AAB87720.3; -; mRNA.
DR AlphaFoldDB; Q8R500; -.
DR SMR; Q8R500; -.
DR STRING; 10116.ENSRNOP00000052539; -.
DR iPTMnet; Q8R500; -.
DR PhosphoSitePlus; Q8R500; -.
DR jPOST; Q8R500; -.
DR PaxDb; Q8R500; -.
DR PRIDE; Q8R500; -.
DR ABCD; Q8R500; 1 sequenced antibody.
DR RGD; 628843; Mfn2.
DR eggNOG; KOG0448; Eukaryota.
DR InParanoid; Q8R500; -.
DR PhylomeDB; Q8R500; -.
DR Reactome; R-RNO-5205685; PINK1-PRKN Mediated Mitophagy.
DR Reactome; R-RNO-9013419; RHOT2 GTPase cycle.
DR Reactome; R-RNO-983231; Factors involved in megakaryocyte development and platelet production.
DR PRO; PR:Q8R500; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005737; C:cytoplasm; IDA:RGD.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0031306; C:intrinsic component of mitochondrial outer membrane; IDA:UniProtKB.
DR GO; GO:0015630; C:microtubule cytoskeleton; ISO:RGD.
DR GO; GO:0005741; C:mitochondrial outer membrane; IDA:RGD.
DR GO; GO:0005739; C:mitochondrion; IDA:RGD.
DR GO; GO:0005525; F:GTP binding; IMP:RGD.
DR GO; GO:0003924; F:GTPase activity; IBA:GO_Central.
DR GO; GO:0051020; F:GTPase binding; IDA:RGD.
DR GO; GO:0042802; F:identical protein binding; IPI:RGD.
DR GO; GO:0043394; F:proteoglycan binding; IPI:RGD.
DR GO; GO:0031267; F:small GTPase binding; IDA:RGD.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; ISO:RGD.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0001825; P:blastocyst formation; ISO:RGD.
DR GO; GO:0048593; P:camera-type eye morphogenesis; ISO:RGD.
DR GO; GO:0071549; P:cellular response to dexamethasone stimulus; IEP:RGD.
DR GO; GO:0071333; P:cellular response to glucose stimulus; IEP:RGD.
DR GO; GO:0071456; P:cellular response to hypoxia; IEP:RGD.
DR GO; GO:0071479; P:cellular response to ionizing radiation; IEP:RGD.
DR GO; GO:1905232; P:cellular response to L-glutamate; IEP:RGD.
DR GO; GO:0071404; P:cellular response to low-density lipoprotein particle stimulus; IEP:RGD.
DR GO; GO:0071287; P:cellular response to manganese ion; IEP:RGD.
DR GO; GO:0072705; P:cellular response to mercaptoethanol; IEP:RGD.
DR GO; GO:0090650; P:cellular response to oxygen-glucose deprivation; IEP:RGD.
DR GO; GO:0071394; P:cellular response to testosterone stimulus; IEP:RGD.
DR GO; GO:0048312; P:intracellular distribution of mitochondria; IMP:RGD.
DR GO; GO:0008584; P:male gonad development; IEP:RGD.
DR GO; GO:0051560; P:mitochondrial calcium ion homeostasis; IMP:RGD.
DR GO; GO:0008053; P:mitochondrial fusion; IMP:RGD.
DR GO; GO:0007006; P:mitochondrial membrane organization; ISS:UniProtKB.
DR GO; GO:0051646; P:mitochondrion localization; ISO:RGD.
DR GO; GO:0070584; P:mitochondrion morphogenesis; IMP:RGD.
DR GO; GO:0007005; P:mitochondrion organization; IMP:RGD.
DR GO; GO:0000278; P:mitotic cell cycle; IEP:RGD.
DR GO; GO:0010667; P:negative regulation of cardiac muscle cell apoptotic process; IMP:RGD.
DR GO; GO:0045786; P:negative regulation of cell cycle; IMP:RGD.
DR GO; GO:0060548; P:negative regulation of cell death; IMP:RGD.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; IMP:RGD.
DR GO; GO:0045792; P:negative regulation of cell size; IMP:RGD.
DR GO; GO:0060253; P:negative regulation of glial cell proliferation; IMP:RGD.
DR GO; GO:0090258; P:negative regulation of mitochondrial fission; IMP:RGD.
DR GO; GO:1901215; P:negative regulation of neuron death; IMP:RGD.
DR GO; GO:0046580; P:negative regulation of Ras protein signal transduction; ISO:RGD.
DR GO; GO:1903427; P:negative regulation of reactive oxygen species biosynthetic process; IMP:RGD.
DR GO; GO:0090201; P:negative regulation of release of cytochrome c from mitochondria; IMP:RGD.
DR GO; GO:0060299; P:negative regulation of sarcomere organization; IMP:RGD.
DR GO; GO:0048662; P:negative regulation of smooth muscle cell proliferation; IDA:UniProtKB.
DR GO; GO:1904706; P:negative regulation of vascular associated smooth muscle cell proliferation; IMP:RGD.
DR GO; GO:0061734; P:parkin-mediated stimulation of mitophagy in response to mitochondrial depolarization; ISO:RGD.
DR GO; GO:1901857; P:positive regulation of cellular respiration; IMP:RGD.
DR GO; GO:0035563; P:positive regulation of chromatin binding; IMP:RGD.
DR GO; GO:0120162; P:positive regulation of cold-induced thermogenesis; ISS:YuBioLab.
DR GO; GO:0061003; P:positive regulation of dendritic spine morphogenesis; IMP:RGD.
DR GO; GO:2000866; P:positive regulation of estradiol secretion; IMP:RGD.
DR GO; GO:0010628; P:positive regulation of gene expression; IMP:RGD.
DR GO; GO:0046326; P:positive regulation of glucose import; IMP:RGD.
DR GO; GO:0010729; P:positive regulation of hydrogen peroxide biosynthetic process; IMP:RGD.
DR GO; GO:0046628; P:positive regulation of insulin receptor signaling pathway; IMP:RGD.
DR GO; GO:0010918; P:positive regulation of mitochondrial membrane potential; IMP:RGD.
DR GO; GO:2000386; P:positive regulation of ovarian follicle development; IMP:RGD.
DR GO; GO:2000872; P:positive regulation of progesterone secretion; IMP:RGD.
DR GO; GO:1903428; P:positive regulation of reactive oxygen species biosynthetic process; IMP:RGD.
DR GO; GO:1905461; P:positive regulation of vascular associated smooth muscle cell apoptotic process; ISO:RGD.
DR GO; GO:1904707; P:positive regulation of vascular associated smooth muscle cell proliferation; ISO:RGD.
DR GO; GO:0034497; P:protein localization to phagophore assembly site; ISO:RGD.
DR GO; GO:0006626; P:protein targeting to mitochondrion; ISS:UniProtKB.
DR GO; GO:0048678; P:response to axon injury; IEP:RGD.
DR GO; GO:0046686; P:response to cadmium ion; IEP:RGD.
DR GO; GO:0051592; P:response to calcium ion; IEP:RGD.
DR GO; GO:1905377; P:response to D-galactose; IEP:RGD.
DR GO; GO:0051602; P:response to electrical stimulus; IEP:RGD.
DR GO; GO:0070542; P:response to fatty acid; IEP:RGD.
DR GO; GO:1905395; P:response to flavonoid; IEP:RGD.
DR GO; GO:1990910; P:response to hypobaric hypoxia; IEP:RGD.
DR GO; GO:1903576; P:response to L-arginine; IEP:RGD.
DR GO; GO:0014850; P:response to muscle activity; IEP:RGD.
DR GO; GO:0031667; P:response to nutrient levels; IEP:RGD.
DR GO; GO:0033574; P:response to testosterone; IEP:RGD.
DR GO; GO:0006986; P:response to unfolded protein; IEA:UniProtKB-KW.
DR GO; GO:0007283; P:spermatogenesis; IEP:RGD.
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 Apoptosis; Autophagy; Coiled coil; GTP-binding; Hydrolase; Membrane;
KW Mitochondrion; Mitochondrion outer membrane; Nucleotide-binding;
KW Phosphoprotein; Reference proteome; Transmembrane; Transmembrane helix;
KW Ubl conjugation; Unfolded protein response.
FT CHAIN 1..757
FT /note="Mitofusin-2"
FT /id="PRO_0000127677"
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 406..435
FT /evidence="ECO:0000255"
FT COILED 696..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:0000250|UniProtKB:O95140"
FT MOD_RES 442
FT /note="Phosphoserine; by PINK1"
FT /evidence="ECO:0000250|UniProtKB:O95140"
FT MUTAGEN 109
FT /note="K->T: Induces mitochondria fragmentation when
FT overexpressed."
FT /evidence="ECO:0000269|PubMed:14561718"
FT CONFLICT 183
FT /note="W -> L (in Ref. 2; AAB87720)"
FT /evidence="ECO:0000305"
FT CONFLICT 194
FT /note="G -> D (in Ref. 2; AAB87720)"
FT /evidence="ECO:0000305"
FT CONFLICT 265
FT /note="S -> P (in Ref. 2; AAB87720)"
FT /evidence="ECO:0000305"
FT CONFLICT 404
FT /note="I -> M (in Ref. 2; AAB87720)"
FT /evidence="ECO:0000305"
FT CONFLICT 431
FT /note="S -> T (in Ref. 2; AAB87720)"
FT /evidence="ECO:0000305"
FT CONFLICT 756
FT /note="S -> G (in Ref. 2; AAB87720)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 757 AA; 86123 MW; BE8340E0891A7DF4 CRC64;
MSLLFSRCNS IVTVKKDKRH MAEVNASPLK HFVTAKKKIN GIFEQLGAYI QESAGFLEDT
HRNTELDPVT TEEQVLDVKG YLSKVRGISE VLARRHMKVA FFGRTSNGKS TVINAMLWDK
VLPSGIGHTT NCFLRVGGTD GHEAFLLTEG SEEKKSVKTV NQLAHALHQD EQLHAGSLVS
VMWPNSKCPL LKDGLVLMDS PGIDVTTELD SWIDKFCLDA DVFVLVANSE STLMQTEKQF
FHKVSERLSR PNIFILNNRW DASASEPEYM EEVRRQHMER CTSFLVDELG VVDRAQAGDR
IFFVSAKEVL SARVQKAQGM PEGGGALAEG FQVRMFEFQN FERRFEECIS QSAVKTKFEQ
HTVRAKQIAE AVRLIMDSLH IAAQEQRVYC LEMREERQDR LRFIDKQLEL LAQDYKLRIK
QMTEEVERQV STAMAEEIRR LSVLVDEYQM DFHPSPVVLK VYKNELHRHI EEGLGRNMSD
RCSTAIASSL QTMQQDMIDG LKPLLPVSVR NQIDMLVPRQ CFSLSYDLNC DKLCADFQED
IEFHFSLGWT MLVNRFLGPK NSRRALLGYN DQVQRPLPLT PANPSMPPLP QGSLTQEELM
VSMVTGLASL TSRTSMGILV VGGVVWKAVG WRLIALSFGL YGLLYVYERL TWTTRAKERA
FKRQFVEYAS EKLQLIISYT GSNCSHQVQQ ELSGTFAHLC QQVDITRDNL EQEIAAMNKK
VEALDSLQSK AKLLRNKAGW LDSELNMFIH QYLQPSR
