MAFB1_TOXGO
ID MAFB1_TOXGO Reviewed; 446 AA.
AC A0A140H546; A0A7J6KGH8;
DT 03-AUG-2022, integrated into UniProtKB/Swiss-Prot.
DT 11-MAY-2016, sequence version 1.
DT 03-AUG-2022, entry version 13.
DE RecName: Full=Mitochondrial association factor 1 form b1 {ECO:0000303|PubMed:26920761};
DE Short=MAF1RHb1 allele {ECO:0000303|PubMed:26920761};
DE AltName: Full=MAF1b {ECO:0000303|PubMed:28567444};
DE Flags: Precursor;
GN Name=MAF1b1 {ECO:0000303|PubMed:26920761};
GN Synonyms=MAF1 {ECO:0000303|PubMed:26920761};
GN ORFNames=TGRH88_000130 {ECO:0000312|EMBL:KAF4645526.1};
OS Toxoplasma gondii.
OC Eukaryota; Sar; Alveolata; Apicomplexa; Conoidasida; Coccidia;
OC Eucoccidiorida; Eimeriorina; Sarcocystidae; Toxoplasma.
OX NCBI_TaxID=5811 {ECO:0000312|Proteomes:UP000557509};
RN [1] {ECO:0000312|EMBL:AMN92247.1}
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], NOMENCLATURE, FUNCTION, SUBCELLULAR
RP LOCATION, DEVELOPMENTAL STAGE, AND POLYMORPHISM.
RC STRAIN=RH {ECO:0000312|EMBL:AMN92247.1};
RX PubMed=26920761; DOI=10.1534/genetics.115.186270;
RA Adomako-Ankomah Y., English E.D., Danielson J.J., Pernas L.F., Parker M.L.,
RA Boulanger M.J., Dubey J.P., Boyle J.P.;
RT "Host Mitochondrial Association Evolved in the Human Parasite Toxoplasma
RT gondii via Neofunctionalization of a Gene Duplicate.";
RL Genetics 203:283-298(2016).
RN [2] {ECO:0000312|Proteomes:UP000557509}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=RH-88 {ECO:0000312|Proteomes:UP000557509};
RA Lorenzi H.A., Venepally P., Rozenberg A., Sibley D.;
RT "Genome sequence of Toxoplasma gondii RH-88 strain.";
RL Submitted (MAR-2020) to the EMBL/GenBank/DDBJ databases.
RN [3] {ECO:0000305}
RP FUNCTION, SUBCELLULAR LOCATION, DEVELOPMENTAL STAGE, POLYMORPHISM,
RP PHOSPHORYLATION, DISRUPTION PHENOTYPE, AND TOPOLOGY.
RC STRAIN=RH {ECO:0000269|PubMed:24781109};
RX PubMed=24781109; DOI=10.1371/journal.pbio.1001845;
RA Pernas L., Adomako-Ankomah Y., Shastri A.J., Ewald S.E., Treeck M.,
RA Boyle J.P., Boothroyd J.C.;
RT "Toxoplasma effector MAF1 mediates recruitment of host mitochondria and
RT impacts the host response.";
RL PLoS Biol. 12:e1001845-e1001845(2014).
RN [4] {ECO:0000305}
RP FUNCTION, INTERACTION WITH HOST MIB COMPLEX AND HOST SAMM50, SUBCELLULAR
RP LOCATION, AND DISRUPTION PHENOTYPE.
RC STRAIN=RH {ECO:0000269|PubMed:28567444};
RX PubMed=28567444; DOI=10.1128/msphere.00183-17;
RA Kelly F.D., Wei B.M., Cygan A.M., Parker M.L., Boulanger M.J.,
RA Boothroyd J.C.;
RT "Toxoplasma gondii MAF1b Binds the Host Cell MIB Complex To Mediate
RT Mitochondrial Association.";
RL MSphere 2:0-0(2017).
RN [5] {ECO:0000305}
RP FUNCTION.
RX PubMed=30333181; DOI=10.1128/msphere.00471-18;
RA English E.D., Boyle J.P.;
RT "Impact of Engineered Expression of Mitochondrial Association Factor 1b on
RT Toxoplasma gondii Infection and the Host Response in a Mouse Model.";
RL MSphere 3:0-0(2018).
RN [6] {ECO:0000305}
RP FUNCTION, INTERACTION WITH HOST TOMM70, AND MUTAGENESIS OF
RP 438-SER--LEU-441.
RX PubMed=33723040; DOI=10.1073/pnas.2013336118;
RA Blank M.L., Xia J., Morcos M.M., Sun M., Cantrell P.S., Liu Y., Zeng X.,
RA Powell C.J., Yates N., Boulanger M.J., Boyle J.P.;
RT "Toxoplasma gondii association with host mitochondria requires key
RT mitochondrial protein import machinery.";
RL Proc. Natl. Acad. Sci. U.S.A. 118:0-0(2021).
RN [7] {ECO:0000305}
RP FUNCTION, INTERACTION WITH HOST TOMM70, DISRUPTION PHENOTYPE, AND
RP MUTAGENESIS OF 438-SER--LEU-441.
RX PubMed=35025629; DOI=10.1126/science.abi4343;
RA Li X., Straub J., Medeiros T.C., Mehra C., den Brave F., Peker E.,
RA Atanassov I., Stillger K., Michaelis J.B., Burbridge E., Adrain C.,
RA Muench C., Riemer J., Becker T., Pernas L.F.;
RT "Mitochondria shed their outer membrane in response to infection-induced
RT stress.";
RL Science 375:eabi4343-eabi4343(2022).
RN [8] {ECO:0007744|PDB:6BXR, ECO:0007744|PDB:6BXW}
RP X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) OF 173-443, FUNCTION, DOMAIN,
RP INTERACTION WITH HOST SAMM50, POLYMORPHISM, AND MUTAGENESIS OF
RP 152-PRO--PRO-164; SER-158; SER-339; 431-HIS--ASP-446 AND 438-SER--LEU-441.
RX PubMed=29505111; DOI=10.1111/mmi.13947;
RA Blank M.L., Parker M.L., Ramaswamy R., Powell C.J., English E.D.,
RA Adomako-Ankomah Y., Pernas L.F., Workman S.D., Boothroyd J.C.,
RA Boulanger M.J., Boyle J.P.;
RT "A Toxoplasma gondii locus required for the direct manipulation of host
RT mitochondria has maintained multiple ancestral functions.";
RL Mol. Microbiol. 108:519-535(2018).
CC -!- FUNCTION: During host cell infection by tachyzoites, required for
CC tethering the parasitophorous vacuole to the host mitochondria
CC (PubMed:26920761, PubMed:24781109, PubMed:28567444, PubMed:33723040,
CC PubMed:35025629, PubMed:29505111). This process, known as host
CC mitochondrial association (HMA), induces the formation of SPOTs
CC (structures positive for outer mitochondrial membrane (OMM)), a
CC cellular response to OMM stress, which leads to the constitutive
CC shedding of OMM vesicles containing proteins such as mitofusins MFN1
CC and MFN2, which normally restrict parasite growth (PubMed:35025629).
CC Specifically, binds to the host OMM import receptor TOMM70 to interact
CC with SAMM50, a component of host mitochondrial intermembrane space
CC bridging (MIB) complex (PubMed:28567444, PubMed:33723040,
CC PubMed:35025629). By targeting SAMM50, induces the disassembly of the
CC MIB complex, thereby promoting the formation of SPOTs
CC (PubMed:35025629). Inhibits host TOMM70 import activity
CC (PubMed:35025629). Plays a role in the modulation of the host innate
CC immune response to parasite infection (PubMed:24781109,
CC PubMed:30333181). {ECO:0000269|PubMed:24781109,
CC ECO:0000269|PubMed:26920761, ECO:0000269|PubMed:28567444,
CC ECO:0000269|PubMed:29505111, ECO:0000269|PubMed:30333181,
CC ECO:0000269|PubMed:33723040, ECO:0000269|PubMed:35025629}.
CC -!- SUBUNIT: Associates with the host mitochondrial intermembrane space
CC bridging (MIB) complex (PubMed:28567444). Interacts with host import
CC receptor TOMM70; the interaction impairs TOMM70 import activity and
CC enables the parasite to associate with the host mitochondria and then
CC with SAMM50; the interaction is likely to be indirect (PubMed:33723040,
CC PubMed:35025629). Interacts with host MIB complex component SAMM50; the
CC interaction requires prior binding to host import receptor TOMM70 and
CC is likely to be indirect (PubMed:28567444, PubMed:29505111).
CC {ECO:0000269|PubMed:28567444, ECO:0000269|PubMed:29505111,
CC ECO:0000269|PubMed:33723040, ECO:0000269|PubMed:35025629}.
CC -!- SUBCELLULAR LOCATION: Parasitophorous vacuole membrane
CC {ECO:0000269|PubMed:24781109, ECO:0000269|PubMed:26920761,
CC ECO:0000269|PubMed:28567444}; Single-pass type I membrane protein
CC {ECO:0000305|PubMed:24781109}. Cytoplasmic granule membrane
CC {ECO:0000269|PubMed:24781109}; Single-pass type I membrane protein
CC {ECO:0000305|PubMed:24781109}. Note=Localizes to dense granules
CC (PubMed:24781109). Localizes at the interface between the
CC parasitophorous vacuole and the host outer mitochondrial membrane
CC (PubMed:26920761, PubMed:24781109). {ECO:0000269|PubMed:24781109,
CC ECO:0000269|PubMed:26920761}.
CC -!- DEVELOPMENTAL STAGE: Expressed in tachyzoites (at protein level).
CC {ECO:0000269|PubMed:24781109, ECO:0000269|PubMed:26920761}.
CC -!- DOMAIN: The proline-rich region is not required for host mitochondrial
CC association (HMA). {ECO:0000269|PubMed:29505111}.
CC -!- PTM: Phosphorylated. {ECO:0000269|PubMed:24781109}.
CC -!- POLYMORPHISM: The MAF1 locus encodes multiple tandemly duplicated
CC paralogs that vary in expression, sequence and copy number across
CC T.gondii strains (PubMed:26920761, PubMed:24781109). For instance, type
CC I strain GT1 has 6 copies, type I strain RH has 4 copies, type II
CC strains ME49 and PRU have 4 copies, type III strain VEG has 4 copies
CC and type III strain CTG has only 2 copies (PubMed:26920761). The
CC paralogs are classified into two groups, a and b and have probably
CC arisen from the neofunctionalization of an ancestral MAF1 a gene
CC (PubMed:26920761). They are characterized by the presence or absence of
CC a repetitive stretch of 4 to 7 prolines followed by a serine (P(4:7)S),
CC as well as differences in the amino acids surrounding the proline motif
CC (PubMed:26920761). This motif is either completely missing (a and b0
CC paralogs) or repeated up to six times (b paralogs) (PubMed:26920761).
CC cross the strains, transcript levels for the a paralogs are similar,
CC however, in type II strain ME49, transcript levels for the b paralogs
CC are low and no paralog MAF1 b1 protein is produced (PubMed:26920761,
CC PubMed:24781109). Paralogs differ in their ability to mediate host
CC mitochondrial association (HMA), but also in their ability to confer a
CC selective advantage during infection in a mouse model (PubMed:26920761,
CC PubMed:24781109, PubMed:29505111). Tachyzoites from type I and III
CC strains associate with host mitochondria (HMA(+)), while tachyzoites
CC from type II strains, such as ME49, do not associate with host
CC mitochondria (HMA(-)) due to a lack of MAF1 b1 expression
CC (PubMed:26920761, PubMed:24781109). {ECO:0000269|PubMed:24781109,
CC ECO:0000269|PubMed:26920761, ECO:0000269|PubMed:29505111}.
CC -!- DISRUPTION PHENOTYPE: Deletion of the whole MAF1 locus (which includes
CC all a and b paralogs) causes a loss in tachyzoite parasitophorous
CC vacuole association with host mitochondria (HMA) upon host infection
CC without causing any significant growth defect to the parasite
CC (PubMed:24781109, PubMed:28567444). Prevents the formation of SPOTs
CC (structures positive for outer mitochondrial membrane (OMM))
CC (PubMed:35025629). Partially impairs the reduction in mitochondrial
CC protein abundance caused by infection; specifically, prevents the loss
CC of MFN1, MFN2 and MIRO2 proteins (PubMed:35025629). Intraperitoneal
CC infection of C57BL/6J mice with knockout tachyzoites results in similar
CC mouse lethality and parasite burden compared to infection with wild
CC type parasite (PubMed:24781109). However, levels of several cytokines
CC and chemokines, including IL4 and CCL11/eotaxin from mouse peritoneal
CC exudate cells (PECs) is reduced (PubMed:24781109).
CC {ECO:0000269|PubMed:24781109, ECO:0000269|PubMed:28567444,
CC ECO:0000269|PubMed:35025629}.
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DR EMBL; KU761334; AMN92247.1; -; Genomic_DNA.
DR EMBL; JAAUHK010000187; KAF4645526.1; -; Genomic_DNA.
DR PDB; 6BXR; X-ray; 1.60 A; A=173-443.
DR PDB; 6BXW; X-ray; 1.65 A; A=173-443.
DR PDBsum; 6BXR; -.
DR PDBsum; 6BXW; -.
DR SMR; A0A140H546; -.
DR VEuPathDB; ToxoDB:TGARI_220950; -.
DR VEuPathDB; ToxoDB:TGCAST_387130; -.
DR VEuPathDB; ToxoDB:TGCAST_390500; -.
DR VEuPathDB; ToxoDB:TGCOUG_394550; -.
DR VEuPathDB; ToxoDB:TGDOM2_323100; -.
DR VEuPathDB; ToxoDB:TGDOM2_401920; -.
DR VEuPathDB; ToxoDB:TGFOU_407690; -.
DR VEuPathDB; ToxoDB:TGGT1_220950; -.
DR VEuPathDB; ToxoDB:TGGT1_411470; -.
DR VEuPathDB; ToxoDB:TGMAS_361110; -.
DR VEuPathDB; ToxoDB:TGME49_220950; -.
DR VEuPathDB; ToxoDB:TGME49_279100; -.
DR VEuPathDB; ToxoDB:TGP89_361110; -.
DR VEuPathDB; ToxoDB:TGPRC2_427480; -.
DR VEuPathDB; ToxoDB:TGRH88_000130; -.
DR VEuPathDB; ToxoDB:TGRUB_433890; -.
DR VEuPathDB; ToxoDB:TGVAND_437510; -.
DR VEuPathDB; ToxoDB:TGVEG_279100; -.
DR VEuPathDB; ToxoDB:TGVEG_442370; -.
DR Proteomes; UP000557509; Unassembled WGS sequence.
DR GO; GO:0030659; C:cytoplasmic vesicle membrane; IDA:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0020005; C:symbiont-containing vacuole membrane; IDA:UniProtKB.
PE 1: Evidence at protein level;
KW 3D-structure; Membrane; Phosphoprotein; Signal; Tachyzoite; Transmembrane;
KW Transmembrane helix.
FT SIGNAL 1..20
FT /evidence="ECO:0000255"
FT CHAIN 21..446
FT /note="Mitochondrial association factor 1 form b1"
FT /evidence="ECO:0000255"
FT /id="PRO_5007302455"
FT TOPO_DOM 21..96
FT /note="Vacuolar"
FT /evidence="ECO:0000305|PubMed:24781109"
FT TRANSMEM 97..117
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 118..446
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:24781109"
FT REGION 431..446
FT /note="Necessary but not sufficient for host membrane
FT association (HMA)"
FT /evidence="ECO:0000269|PubMed:29505111"
FT MUTAGEN 152..164
FT /note="PPPPPPSPPPPPP->AAAAAASAAAAAA: No effect on host
FT membrane association (HMA)."
FT /evidence="ECO:0000269|PubMed:29505111"
FT MUTAGEN 158
FT /note="S->A: No effect on host membrane association (HMA)."
FT /evidence="ECO:0000269|PubMed:29505111"
FT MUTAGEN 339
FT /note="S->F: No effect on host membrane association (HMA)."
FT /evidence="ECO:0000269|PubMed:29505111"
FT MUTAGEN 431..446
FT /note="HGLQEAESTYLASMLD->RGLMESERKYKFPQGD: Loss of host
FT membrane association (HMA). Reduces parasite survival
FT and/or growth in an infection mouse model. No effect on the
FT binding to SAMM50."
FT /evidence="ECO:0000269|PubMed:29505111"
FT MUTAGEN 438..441
FT /note="STYL->RKYK: Loss of host membrane association (HMA).
FT Reduces parasite survival and/or growth in an infection
FT mouse model. Loss of interaction with host TOMM70. No
FT effect on the binding to SAMM50. Loss of SPOTs formation."
FT /evidence="ECO:0000269|PubMed:29505111,
FT ECO:0000269|PubMed:33723040, ECO:0000269|PubMed:35025629"
FT CONFLICT 442
FT /note="A -> D (in Ref. 2; KAF4645526)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 446 AA; 47909 MW; A40FCF0E50D19A4C CRC64;
MWRIWRCRLS FLFATGCLLG ALTAGLGSQM SDSVGRNVQA PAGVADASQE AGDVVEERTE
RTEEQAFALG PPRRHSSESL FPRNASVTAR RRRNRRIALI ATAVGVAVIL AAVYVLRRRR
AQRPQDPEPP APRSVEDPEV LPEEDEASSS LPPPPPPSPP PPPPVEDPLS PESQTVDLSC
LSGTTVRFFG PSHHFGGFTP LYDPAPDKRV ATVDAGANAL FIGGGGLNGQ FAKTLLEEAE
KHGIRLTPEE LSQHSQRIQQ SLLRRAVKSP GKLVELDTGV ASPVFARSFG FVPVVPGLMW
EESEVGPNVG VTFVHILKPE VTPYGNLNNN VMMYTVAPSG AAPDKTYSLA YKTTIAGVIG
AAAAYNDTPA GQQYPVQGLR LPLLGGGIFR RNRSLESIGR ANAEGTSLAI TRYGPNFELQ
YMYDPSNAAL HGLQEAESTY LASMLD
