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 12-APR-2017, entry version 19. 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., RA Harris D.E., Gordon S.V., Eiglmeier K., Gas S., Barry C.E. III, RA Tekaia F., Badcock K., Basham D., Brown D., Chillingworth T., RA Connor R., Davies R.M., Devlin K., Feltwell T., Gentles S., Hamlin N., RA Holroyd S., Hornsby T., Jagels K., Krogh A., McLean J., Moule S., RA Murphy L.D., Oliver S., Osborne J., Quail M.A., Rajandream M.A., RA Rogers J., Rutter S., Seeger K., Skelton S., Squares S., Squares R., RA Sulston J.E., Taylor K., Whitehead S., Barrell B.G.; RT "Deciphering the biology of Mycobacterium tuberculosis from the RT complete 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., RA Barry C.E. III; RT "The role of MmpL8 in sulfatide biogenesis and virulence of RT Mycobacterium 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 RT genes 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 RT tuberculosis through an interactome, reactome and genome-scale RT 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., RA Gilmore S.A., Tully S.E., Niederweis M., Cravatt B.F., Leary J.A., RA 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 CC the inner membrane of sulfolipid-1 (SL-1), which is a major cell CC wall lipid of pathogenic mycobacteria. Could also transport SL1278 CC (2-palmitoyl-3-(C43)-phthioceranyl-alpha, alpha'-D-trehalose-2'- CC sulfate), which is the 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 CC containment of this replication in the lung and spleen are CC identical to the wild-type. Inactivation of the mmpL8 gene CC interrupts the normal biosynthesis of SL-1 and leads to the CC 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 CC (RND) (TC 2.A.6) family. MmpL subfamily. {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; AL123456; CCP46652.1; -; Genomic_DNA. DR PIR; C70522; C70522. DR RefSeq; NP_218340.1; NC_000962.3. DR RefSeq; WP_003899710.1; NZ_KK339374.1. DR STRING; 83332.Rv3823c; -. DR PaxDb; P9WJU5; -. DR EnsemblBacteria; CCP46652; CCP46652; Rv3823c. DR GeneID; 886145; -. DR KEGG; mtu:Rv3823c; -. DR KEGG; mtv:RVBD_3823c; -. DR TubercuList; Rv3823c; -. DR eggNOG; ENOG4105EYF; Bacteria. DR eggNOG; COG2409; LUCA. DR KO; K06994; -. DR OMA; RRGWITP; -. DR PhylomeDB; P9WJU5; -. DR Proteomes; UP000001584; Chromosome. DR GO; GO:0005618; C:cell wall; IDA:MTBBASE. DR GO; GO:0005829; C:cytosol; IDA:MTBBASE. DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW. 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 Complete proteome; Lipid transport; Membrane; Reference proteome; KW Transmembrane; Transmembrane helix; Transport. FT CHAIN 1 1089 Sulfolipid-1 exporter MmpL8. FT /FTId=PRO_0000103572. FT TRANSMEM 44 64 Helical. {ECO:0000255}. FT TRANSMEM 222 242 Helical. {ECO:0000255}. FT TRANSMEM 257 277 Helical. {ECO:0000255}. FT TRANSMEM 316 336 Helical. {ECO:0000255}. FT TRANSMEM 349 369 Helical. {ECO:0000255}. FT TRANSMEM 400 420 Helical. {ECO:0000255}. FT TRANSMEM 555 575 Helical. {ECO:0000255}. FT TRANSMEM 874 894 Helical. {ECO:0000255}. FT TRANSMEM 898 918 Helical. {ECO:0000255}. FT TRANSMEM 930 950 Helical. {ECO:0000255}. FT TRANSMEM 973 993 Helical. {ECO:0000255}. FT TRANSMEM 996 1016 Helical. {ECO:0000255}. 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 //