ID   MMPL8_MYCTU             Reviewed;        1089 AA.
AC   P9WJU5; L0TFD0; O07800;
DT   16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT   16-APR-2014, sequence version 1.
DT   03-AUG-2022, entry version 34.
DE   RecName: Full=Sulfolipid-1 exporter MmpL8 {ECO:0000305};
GN   Name=mmpL8; OrderedLocusNames=Rv3823c; ORFNames=MTCY409.07;
OS   Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv).
OC   Bacteria; Actinobacteria; Corynebacteriales; Mycobacteriaceae;
OC   Mycobacterium; Mycobacterium tuberculosis complex.
OX   NCBI_TaxID=83332;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=ATCC 25618 / H37Rv;
RX   PubMed=9634230; DOI=10.1038/31159;
RA   Cole S.T., Brosch R., Parkhill J., Garnier T., Churcher C.M., Harris D.E.,
RA   Gordon S.V., Eiglmeier K., Gas S., Barry C.E. III, Tekaia F., Badcock K.,
RA   Basham D., Brown D., Chillingworth T., Connor R., Davies R.M., Devlin K.,
RA   Feltwell T., Gentles S., Hamlin N., Holroyd S., Hornsby T., Jagels K.,
RA   Krogh A., McLean J., Moule S., Murphy L.D., Oliver S., Osborne J.,
RA   Quail M.A., Rajandream M.A., Rogers J., Rutter S., Seeger K., Skelton S.,
RA   Squares S., Squares R., Sulston J.E., Taylor K., Whitehead S.,
RA   Barrell B.G.;
RT   "Deciphering the biology of Mycobacterium tuberculosis from the complete
RT   genome sequence.";
RL   Nature 393:537-544(1998).
RN   [2]
RP   FUNCTION IN SULFOLIPID-1 BIOSYNTHESIS AND VIRULENCE, AND DISRUPTION
RP   PHENOTYPE.
RC   STRAIN=ATCC 35801 / TMC 107 / Erdman;
RX   PubMed=12724526; DOI=10.1073/pnas.1030024100;
RA   Converse S.E., Mougous J.D., Leavell M.D., Leary J.A., Bertozzi C.R.,
RA   Cox J.S.;
RT   "MmpL8 is required for sulfolipid-1 biosynthesis and Mycobacterium
RT   tuberculosis virulence.";
RL   Proc. Natl. Acad. Sci. U.S.A. 100:6121-6126(2003).
RN   [3]
RP   FUNCTION IN SULFOLIPID-1 BIOSYNTHESIS AND VIRULENCE, AND DISRUPTION
RP   PHENOTYPE.
RC   STRAIN=ATCC 25618 / H37Rv;
RX   PubMed=15001577; DOI=10.1074/jbc.m400324200;
RA   Domenech P., Reed M.B., Dowd C.S., Manca C., Kaplan G., Barry C.E. III;
RT   "The role of MmpL8 in sulfatide biogenesis and virulence of Mycobacterium
RT   tuberculosis.";
RL   J. Biol. Chem. 279:21257-21265(2004).
RN   [4]
RP   FUNCTION IN VIRULENCE.
RC   STRAIN=ATCC 25618 / H37Rv;
RX   PubMed=15908378; DOI=10.1128/iai.73.6.3492-3501.2005;
RA   Domenech P., Reed M.B., Barry C.E. III;
RT   "Contribution of the Mycobacterium tuberculosis MmpL protein family to
RT   virulence and drug resistance.";
RL   Infect. Immun. 73:3492-3501(2005).
RN   [5]
RP   REGULATION BY PHOP/PHOR.
RC   STRAIN=ATCC 25618 / H37Rv;
RX   PubMed=16573683; DOI=10.1111/j.1365-2958.2006.05102.x;
RA   Walters S.B., Dubnau E., Kolesnikova I., Laval F., Daffe M., Smith I.;
RT   "The Mycobacterium tuberculosis PhoPR two-component system regulates genes
RT   essential for virulence and complex lipid biosynthesis.";
RL   Mol. Microbiol. 60:312-330(2006).
RN   [6]
RP   IDENTIFICATION AS A DRUG TARGET [LARGE SCALE ANALYSIS].
RX   PubMed=19099550; DOI=10.1186/1752-0509-2-109;
RA   Raman K., Yeturu K., Chandra N.;
RT   "targetTB: a target identification pipeline for Mycobacterium tuberculosis
RT   through an interactome, reactome and genome-scale structural analysis.";
RL   BMC Syst. Biol. 2:109-109(2008).
RN   [7]
RP   FUNCTION IN SULFOLIPID-1 BIOSYNTHESIS AND TRANSPORT, AND SUBCELLULAR
RP   LOCATION.
RC   STRAIN=ATCC 35801 / TMC 107 / Erdman;
RX   PubMed=22194604; DOI=10.1074/jbc.m111.315473;
RA   Seeliger J.C., Holsclaw C.M., Schelle M.W., Botyanszki Z., Gilmore S.A.,
RA   Tully S.E., Niederweis M., Cravatt B.F., Leary J.A., Bertozzi C.R.;
RT   "Elucidation and chemical modulation of sulfolipid-1 biosynthesis in
RT   Mycobacterium tuberculosis.";
RL   J. Biol. Chem. 287:7990-8000(2012).
CC   -!- FUNCTION: Required for the biosynthesis and the transport across the
CC       inner membrane of sulfolipid-1 (SL-1), which is a major cell wall lipid
CC       of pathogenic mycobacteria. Could also transport SL1278 (2-palmitoyl-3-
CC       (C43)-phthioceranyl-alpha, alpha'-D-trehalose-2'-sulfate), which is the
CC       precursor of SL-1. Required for virulence.
CC       {ECO:0000269|PubMed:12724526, ECO:0000269|PubMed:15001577,
CC       ECO:0000269|PubMed:15908378, ECO:0000269|PubMed:22194604}.
CC   -!- SUBCELLULAR LOCATION: Cell inner membrane
CC       {ECO:0000305|PubMed:22194604}; Multi-pass membrane protein
CC       {ECO:0000255}.
CC   -!- INDUCTION: Up-regulated by the PhoP/PhoR two-component system.
CC       {ECO:0000269|PubMed:16573683}.
CC   -!- DISRUPTION PHENOTYPE: Cells show attenuated virulence in murine
CC       survival studies although initial replication rates and containment of
CC       this replication in the lung and spleen are identical to the wild-type.
CC       Inactivation of the mmpL8 gene interrupts the normal biosynthesis of
CC       SL-1 and leads to the accumulation of the precursor SL1278.
CC       {ECO:0000269|PubMed:12724526, ECO:0000269|PubMed:15001577}.
CC   -!- MISCELLANEOUS: Was identified as a high-confidence drug target.
CC       {ECO:0000269|PubMed:19099550}.
CC   -!- SIMILARITY: Belongs to the resistance-nodulation-cell division (RND)
CC       (TC 2.A.6) family. MmpL subfamily. {ECO:0000305}.
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DR   EMBL; AL123456; CCP46652.1; -; Genomic_DNA.
DR   PIR; C70522; C70522.
DR   RefSeq; NP_218340.1; NC_000962.3.
DR   RefSeq; WP_003899710.1; NZ_NVQJ01000022.1.
DR   AlphaFoldDB; P9WJU5; -.
DR   STRING; 83332.Rv3823c; -.
DR   PaxDb; P9WJU5; -.
DR   DNASU; 886145; -.
DR   GeneID; 886145; -.
DR   KEGG; mtu:Rv3823c; -.
DR   PATRIC; fig|83332.111.peg.4250; -.
DR   TubercuList; Rv3823c; -.
DR   eggNOG; COG1511; Bacteria.
DR   eggNOG; COG2409; Bacteria.
DR   OMA; MAQRVSQ; -.
DR   PhylomeDB; P9WJU5; -.
DR   Proteomes; UP000001584; Chromosome.
DR   GO; GO:0005829; C:cytosol; HDA:MTBBASE.
DR   GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR   GO; GO:0009274; C:peptidoglycan-based cell wall; HDA:MTBBASE.
DR   GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0071555; P:cell wall organization; IEA:UniProtKB-KW.
DR   GO; GO:0006869; P:lipid transport; IEA:UniProtKB-KW.
DR   GO; GO:0046506; P:sulfolipid biosynthetic process; IMP:MTBBASE.
DR   InterPro; IPR004869; MMPL_dom.
DR   InterPro; IPR000731; SSD.
DR   Pfam; PF03176; MMPL; 2.
DR   PROSITE; PS50156; SSD; 1.
PE   1: Evidence at protein level;
KW   Cell inner membrane; Cell membrane; Cell wall biogenesis/degradation;
KW   Lipid transport; Membrane; Reference proteome; Transmembrane;
KW   Transmembrane helix; Transport.
FT   CHAIN           1..1089
FT                   /note="Sulfolipid-1 exporter MmpL8"
FT                   /id="PRO_0000103572"
FT   TRANSMEM        44..64
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        222..242
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        257..277
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        316..336
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        349..369
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        400..420
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        555..575
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        874..894
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        898..918
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        930..950
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        973..993
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        996..1016
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   REGION          1..26
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          1056..1078
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
SQ   SEQUENCE   1089 AA;  115998 MW;  E9F842026831060F CRC64;
     MCDVLMQPVR TPRPSTNLRS KPLRPTGDGG VFPRLGRLIV RRPWVVIAFW VALAGLLAPT
     VPSLDAISQR HPVAILPSDA PVLVSTRQMT AAFREAGLQS VAVVVLSDAK GLGAADERSY
     KELVDALRRD TRDVVMLQDF VTTPPLRELM TSKDNQAWIL PVGLPGDLGS TQSKQAYARV
     ADIVEHQVAG STLTANLTGP AATVADLNLT GQRDRSRIEF AITILLLVIL LIIYGNPITM
     VLPLITIGMS VVVAQRLVAI AGLAGLGIAN QSIIFMSGMM VGAGTDYAVF LISRYHDYLR
     QGADSDQAVK KALTSIGKVI AASAATVAIT FLGMVFTQLG ILKTVGPMLG ISVAVVFFAA
     VTLLPALMVL TGRRGWIAPR RDLTRRFWRS SGVHIVRRPK THLLASALVL VILAGCAGLA
     RYNYDDRKTL PASVESSIGY AALDKHFPSN LIIPEYLFIQ SSTDLRTPKA LADLEQMVQR
     VSQVPGVAMV RGITRPAGRS LEQARTSWQA GEVGSKLDEG SKQIAVHTGD IDKLAGGANL
     MASKLGDVRA QVNRAISTVG GLIDALAYLQ DLLGGNRVLG ELEGAEKLIG SMRALGDTID
     ADASFVANNT EWASPVLGAL DSSPMCTADP ACASARTELQ RLVTARDDGT LAKISELARQ
     LQATRAVQTL AATVSGLRGA LATVIRAMGS LGMSSPGGVR SKINLVNKGV NDLADGSRQL
     AEGVQLLVDQ VKKMGFGLGE ASAFLLAMKD TATTPAMAGF YIPPELLSYA TGESVKAETM
     PSEYRDLLGG LNVDQLKKVA AAFISPDGHS IRYLIQTDLN PFSTAAMDQI DAITAAARGA
     QPNTALADAK VSVVGLPVVL KDTRDYSDHD LRLIIAMTVC IVLLILIVLL RAIVAPLYLI
     GSVIVSYLAA LGIGVIVFQF LLGQEMHWSI PGLTFVILVA VGADYNMLLI SRLREEAVLG
     VRSGVIRTVA STGGVITAAG LIMAASMYGL VFASLGSVVQ GAFVLGTGLL LDTFLVRTVT
     VPAIAVLVGQ ANWWLPSSWR PATWWPLGRR RGRAQRTKRK PLLPKEEEEQ SPPDDDDLIG
     LWLHDGLRL