TIMP_DROME
ID TIMP_DROME Reviewed; 210 AA.
AC Q9VH14; A4V2N5; O96747;
DT 20-JUN-2002, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2000, sequence version 1.
DT 03-AUG-2022, entry version 158.
DE RecName: Full=Tissue inhibitor of metalloproteinase {ECO:0000303|PubMed:10198170};
DE Flags: Precursor;
GN Name=Timp {ECO:0000303|PubMed:10198170, ECO:0000312|EMBL:AAN13465.1,
GN ECO:0000312|FlyBase:FBgn0025879};
GN ORFNames=CG6281 {ECO:0000312|FlyBase:FBgn0025879};
OS Drosophila melanogaster (Fruit fly).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Hexapoda; Insecta; Pterygota;
OC Neoptera; Endopterygota; Diptera; Brachycera; Muscomorpha; Ephydroidea;
OC Drosophilidae; Drosophila; Sophophora.
OX NCBI_TaxID=7227;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Canton-S; TISSUE=Head;
RX PubMed=10198170; DOI=10.1006/geno.1999.5776;
RA Pohar N., Godenschwege T.A., Buchner E.;
RT "Invertebrate tissue inhibitor of metalloproteinase: structure and nested
RT gene organization within the synapsin locus is conserved from Drosophila to
RT human.";
RL Genomics 57:293-296(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Berkeley;
RX PubMed=10731132; DOI=10.1126/science.287.5461.2185;
RA Adams M.D., Celniker S.E., Holt R.A., Evans C.A., Gocayne J.D.,
RA Amanatides P.G., Scherer S.E., Li P.W., Hoskins R.A., Galle R.F.,
RA George R.A., Lewis S.E., Richards S., Ashburner M., Henderson S.N.,
RA Sutton G.G., Wortman J.R., Yandell M.D., Zhang Q., Chen L.X., Brandon R.C.,
RA Rogers Y.-H.C., Blazej R.G., Champe M., Pfeiffer B.D., Wan K.H., Doyle C.,
RA Baxter E.G., Helt G., Nelson C.R., Miklos G.L.G., Abril J.F., Agbayani A.,
RA An H.-J., Andrews-Pfannkoch C., Baldwin D., Ballew R.M., Basu A.,
RA Baxendale J., Bayraktaroglu L., Beasley E.M., Beeson K.Y., Benos P.V.,
RA Berman B.P., Bhandari D., Bolshakov S., Borkova D., Botchan M.R., Bouck J.,
RA Brokstein P., Brottier P., Burtis K.C., Busam D.A., Butler H., Cadieu E.,
RA Center A., Chandra I., Cherry J.M., Cawley S., Dahlke C., Davenport L.B.,
RA Davies P., de Pablos B., Delcher A., Deng Z., Mays A.D., Dew I.,
RA Dietz S.M., Dodson K., Doup L.E., Downes M., Dugan-Rocha S., Dunkov B.C.,
RA Dunn P., Durbin K.J., Evangelista C.C., Ferraz C., Ferriera S.,
RA Fleischmann W., Fosler C., Gabrielian A.E., Garg N.S., Gelbart W.M.,
RA Glasser K., Glodek A., Gong F., Gorrell J.H., Gu Z., Guan P., Harris M.,
RA Harris N.L., Harvey D.A., Heiman T.J., Hernandez J.R., Houck J., Hostin D.,
RA Houston K.A., Howland T.J., Wei M.-H., Ibegwam C., Jalali M., Kalush F.,
RA Karpen G.H., Ke Z., Kennison J.A., Ketchum K.A., Kimmel B.E., Kodira C.D.,
RA Kraft C.L., Kravitz S., Kulp D., Lai Z., Lasko P., Lei Y., Levitsky A.A.,
RA Li J.H., Li Z., Liang Y., Lin X., Liu X., Mattei B., McIntosh T.C.,
RA McLeod M.P., McPherson D., Merkulov G., Milshina N.V., Mobarry C.,
RA Morris J., Moshrefi A., Mount S.M., Moy M., Murphy B., Murphy L.,
RA Muzny D.M., Nelson D.L., Nelson D.R., Nelson K.A., Nixon K., Nusskern D.R.,
RA Pacleb J.M., Palazzolo M., Pittman G.S., Pan S., Pollard J., Puri V.,
RA Reese M.G., Reinert K., Remington K., Saunders R.D.C., Scheeler F.,
RA Shen H., Shue B.C., Siden-Kiamos I., Simpson M., Skupski M.P., Smith T.J.,
RA Spier E., Spradling A.C., Stapleton M., Strong R., Sun E., Svirskas R.,
RA Tector C., Turner R., Venter E., Wang A.H., Wang X., Wang Z.-Y.,
RA Wassarman D.A., Weinstock G.M., Weissenbach J., Williams S.M., Woodage T.,
RA Worley K.C., Wu D., Yang S., Yao Q.A., Ye J., Yeh R.-F., Zaveri J.S.,
RA Zhan M., Zhang G., Zhao Q., Zheng L., Zheng X.H., Zhong F.N., Zhong W.,
RA Zhou X., Zhu S.C., Zhu X., Smith H.O., Gibbs R.A., Myers E.W., Rubin G.M.,
RA Venter J.C.;
RT "The genome sequence of Drosophila melanogaster.";
RL Science 287:2185-2195(2000).
RN [3]
RP GENOME REANNOTATION.
RC STRAIN=Berkeley;
RX PubMed=12537572; DOI=10.1186/gb-2002-3-12-research0083;
RA Misra S., Crosby M.A., Mungall C.J., Matthews B.B., Campbell K.S.,
RA Hradecky P., Huang Y., Kaminker J.S., Millburn G.H., Prochnik S.E.,
RA Smith C.D., Tupy J.L., Whitfield E.J., Bayraktaroglu L., Berman B.P.,
RA Bettencourt B.R., Celniker S.E., de Grey A.D.N.J., Drysdale R.A.,
RA Harris N.L., Richter J., Russo S., Schroeder A.J., Shu S.Q., Stapleton M.,
RA Yamada C., Ashburner M., Gelbart W.M., Rubin G.M., Lewis S.E.;
RT "Annotation of the Drosophila melanogaster euchromatic genome: a systematic
RT review.";
RL Genome Biol. 3:RESEARCH0083.1-RESEARCH0083.22(2002).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=Berkeley; TISSUE=Head;
RX PubMed=12537569; DOI=10.1186/gb-2002-3-12-research0080;
RA Stapleton M., Carlson J.W., Brokstein P., Yu C., Champe M., George R.A.,
RA Guarin H., Kronmiller B., Pacleb J.M., Park S., Wan K.H., Rubin G.M.,
RA Celniker S.E.;
RT "A Drosophila full-length cDNA resource.";
RL Genome Biol. 3:RESEARCH0080.1-RESEARCH0080.8(2002).
RN [5]
RP PROTEIN SEQUENCE OF 28-40, FUNCTION, SUBCELLULAR LOCATION, AND 3D-STRUCTURE
RP MODELING AND CIRCULAR DICHROISM ANALYSIS OF THE N-TERMINAL INHIBITORY
RP DOMAIN.
RX PubMed=14567681; DOI=10.1021/bi035358x;
RA Wei S., Xie Z., Filenova E., Brew K.;
RT "Drosophila TIMP is a potent inhibitor of MMPs and TACE: similarities in
RT structure and function to TIMP-3.";
RL Biochemistry 42:12200-12207(2003).
RN [6]
RP TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, AND DISRUPTION PHENOTYPE.
RX PubMed=10961449; DOI=10.1078/0171-9335-00072;
RA Godenschwege T.A., Pohar N., Buchner S., Buchner E.;
RT "Inflated wings, tissue autolysis and early death in tissue inhibitor of
RT metalloproteinases mutants of Drosophila.";
RL Eur. J. Cell Biol. 79:495-501(2000).
RN [7]
RP FUNCTION, TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE.
RX PubMed=16962574; DOI=10.1016/j.ydbio.2006.08.011;
RA Kiger J.A. Jr., Natzle J.E., Kimbrell D.A., Paddy M.R., Kleinhesselink K.,
RA Green M.M.;
RT "Tissue remodeling during maturation of the Drosophila wing.";
RL Dev. Biol. 301:178-191(2007).
RN [8]
RP FUNCTION.
RX PubMed=17301221; DOI=10.1073/pnas.0611666104;
RA Srivastava A., Pastor-Pareja J.C., Igaki T., Pagliarini R., Xu T.;
RT "Basement membrane remodeling is essential for Drosophila disc eversion and
RT tumor invasion.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:2721-2726(2007).
RN [9]
RP FUNCTION, TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE.
RX PubMed=26808525; DOI=10.1371/journal.pgen.1005763;
RA Pearson J.R., Zurita F., Tomas-Gallardo L., Diaz-Torres A.,
RA Diaz de la Loza M., Franze K., Martin-Bermudo M.D., Gonzalez-Reyes A.;
RT "ECM-regulator timp is required for stem cell niche organization and cyst
RT production in the Drosophila ovary.";
RL PLoS Genet. 12:E1005763-E1005763(2016).
CC -!- FUNCTION: Metalloproteinase inhibitor that acts on both matrix
CC metalloproteinases Mmp1 and Mmp2 in vitro (PubMed:14567681). Complexes
CC with metalloproteinases and irreversibly inactivates them by binding to
CC their catalytic zinc cofactor (By similarity). Required for wing
CC maturation which is the final step in morphogenesis of the adult fly
CC (PubMed:16962574). Involved in the negative regulation of developmental
CC tissue invasion for imaginal disk eversion during metamorphosis by
CC inhibiting Mmp-mediated basement membrane (BM) degradation
CC (PubMed:17301221). Required for oogenesis and for the long-term
CC maintainance of germarial structure and shape in the adult ovaries.
CC Required for maintaining composition and biophysical properties of the
CC extracellular matrix (ECM), and for the normal organization and cyst
CC production of the germline stem cell (GSC) niche (PubMed:26808525).
CC {ECO:0000250|UniProtKB:P16035, ECO:0000269|PubMed:14567681,
CC ECO:0000269|PubMed:16962574, ECO:0000269|PubMed:17301221,
CC ECO:0000269|PubMed:26808525}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:14567681}.
CC -!- TISSUE SPECIFICITY: Expressed in heads of female and male adult flies
CC (PubMed:10961449). Expressed at the time of eclosion in unopened wings
CC of adult flies (PubMed:16962574). Strongly expressed at the tip of
CC ovarian germarium region 1 where germline stem cells (GSCs) and
CC cystoblasts reside and in region 2 of the germarium (PubMed:26808525).
CC {ECO:0000269|PubMed:10961449, ECO:0000269|PubMed:16962574,
CC ECO:0000269|PubMed:26808525}.
CC -!- DEVELOPMENTAL STAGE: Expressed throughout development in larvae and
CC pupae. Expressed at embryonic stage 14-17 in a small constriction of
CC the gut, in the full complement of cardial cells and in a paired
CC anterior structure, possibly belonging to the antenno-maxillary
CC complex. {ECO:0000269|PubMed:10961449}.
CC -!- DISRUPTION PHENOTYPE: Adult flies display wings inflated with lymph,
CC suffer from a bloated gut and progressive dissolution of internal
CC tissues, have reduced fertility, show impaired fast phototactic
CC responses, and die prematurely (PubMed:10961449). Flies display wings
CC with fluid filled blisters approximately 22 hours after eclosion
CC resulting from failure of dorsal and ventral cuticular wing surfaces to
CC bond following normal migration of the epithelial cells from the wing
CC (PubMed:16962574). Female flies are sub-viable, semi-sterile and grow
CC smaller ovaries. Ovaries show cellular degeneration with escort cells
CC and follicle cells often displaying clear cytoplasms, multi-lamellar
CC bodies and multi-vesicular vacuoles containing cell debris. Ovaries
CC have reduced levels of both extracellular matrix (ECM) collagen IV
CC alpha chains. Reduced tissue stiffness along germaria of ovarioles,
CC including the germline stem cell (GSC) niche and the area where the
CC follicle stem cells reside, as well as in the follicular epithelium of
CC early egg chambers and their interfollicular stalks, despite a largely
CC normal distribution of major ECM components. Severely impaired
CC oogenesis, abnormally long interfollicular stalks, significant
CC alterations to germarium morphology and abnormalities in stem cell
CC niche organization in aging ovaries. Impaired ability of the GSC niche
CC to generate new cysts. Abnormal localization of matrix
CC metalloproteinases Mmp1 and Mmp2 (PubMed:26808525).
CC {ECO:0000269|PubMed:10961449, ECO:0000269|PubMed:16962574,
CC ECO:0000269|PubMed:26808525}.
CC -!- SIMILARITY: Belongs to the protease inhibitor I35 (TIMP) family.
CC {ECO:0000305}.
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DR EMBL; AJ010067; CAA08989.1; -; mRNA.
DR EMBL; AE014297; AAF54507.1; -; Genomic_DNA.
DR EMBL; AE014297; AAN13465.1; -; Genomic_DNA.
DR EMBL; AY069211; AAL39356.1; -; mRNA.
DR RefSeq; NP_731461.1; NM_169336.4.
DR AlphaFoldDB; Q9VH14; -.
DR SMR; Q9VH14; -.
DR BioGRID; 66397; 10.
DR IntAct; Q9VH14; 1.
DR STRING; 7227.FBpp0081722; -.
DR MEROPS; I35.005; -.
DR PaxDb; Q9VH14; -.
DR PRIDE; Q9VH14; -.
DR DNASU; 41248; -.
DR EnsemblMetazoa; FBtr0082245; FBpp0081722; FBgn0025879.
DR GeneID; 41248; -.
DR KEGG; dme:Dmel_CG6281; -.
DR CTD; 41248; -.
DR FlyBase; FBgn0025879; Timp.
DR VEuPathDB; VectorBase:FBgn0025879; -.
DR eggNOG; KOG4745; Eukaryota.
DR GeneTree; ENSGT00940000169308; -.
DR HOGENOM; CLU_084029_0_0_1; -.
DR InParanoid; Q9VH14; -.
DR OMA; KKCLSYP; -.
DR OrthoDB; 1122531at2759; -.
DR PhylomeDB; Q9VH14; -.
DR Reactome; R-DME-114608; Platelet degranulation.
DR Reactome; R-DME-1592389; Activation of Matrix Metalloproteinases.
DR Reactome; R-DME-381426; Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs).
DR Reactome; R-DME-6798695; Neutrophil degranulation.
DR Reactome; R-DME-8957275; Post-translational protein phosphorylation.
DR SignaLink; Q9VH14; -.
DR BioGRID-ORCS; 41248; 0 hits in 3 CRISPR screens.
DR GenomeRNAi; 41248; -.
DR PRO; PR:Q9VH14; -.
DR Proteomes; UP000000803; Chromosome 3R.
DR Bgee; FBgn0025879; Expressed in oviduct (Drosophila) and 27 other tissues.
DR Genevisible; Q9VH14; DM.
DR GO; GO:0030425; C:dendrite; IMP:FlyBase.
DR GO; GO:0031012; C:extracellular matrix; IBA:GO_Central.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:0008191; F:metalloendopeptidase inhibitor activity; IDA:FlyBase.
DR GO; GO:0002020; F:protease binding; IBA:GO_Central.
DR GO; GO:0008270; F:zinc ion binding; ISS:UniProtKB.
DR GO; GO:0071711; P:basement membrane organization; IMP:FlyBase.
DR GO; GO:0007155; P:cell adhesion; IMP:FlyBase.
DR GO; GO:0060232; P:delamination; IMP:FlyBase.
DR GO; GO:0048526; P:imaginal disc-derived wing expansion; IMP:FlyBase.
DR GO; GO:0010951; P:negative regulation of endopeptidase activity; IBA:GO_Central.
DR GO; GO:0051045; P:negative regulation of membrane protein ectodomain proteolysis; IBA:GO_Central.
DR GO; GO:0048477; P:oogenesis; IEA:UniProtKB-KW.
DR GO; GO:0042331; P:phototaxis; IMP:FlyBase.
DR GO; GO:0010033; P:response to organic substance; IBA:GO_Central.
DR GO; GO:0007426; P:tracheal outgrowth, open tracheal system; IMP:FlyBase.
DR GO; GO:0035202; P:tracheal pit formation in open tracheal system; IMP:FlyBase.
DR GO; GO:0007419; P:ventral cord development; IMP:FlyBase.
DR GO; GO:0007472; P:wing disc morphogenesis; IMP:FlyBase.
DR Gene3D; 2.40.50.120; -; 1.
DR Gene3D; 3.90.370.10; -; 1.
DR InterPro; IPR001134; Netrin_domain.
DR InterPro; IPR001820; TIMP.
DR InterPro; IPR008993; TIMP-like_OB-fold.
DR InterPro; IPR027465; TIMP_C.
DR PANTHER; PTHR11844; PTHR11844; 1.
DR Pfam; PF00965; TIMP; 1.
DR SMART; SM00206; NTR; 1.
DR SUPFAM; SSF50242; SSF50242; 1.
DR PROSITE; PS50189; NTR; 1.
PE 1: Evidence at protein level;
KW Developmental protein; Differentiation; Direct protein sequencing;
KW Disulfide bond; Metal-binding; Metalloenzyme inhibitor;
KW Metalloprotease inhibitor; Oogenesis; Protease inhibitor;
KW Reference proteome; Secreted; Signal; Zinc.
FT SIGNAL 1..27
FT /evidence="ECO:0000269|PubMed:14567681"
FT CHAIN 28..210
FT /note="Tissue inhibitor of metalloproteinase"
FT /id="PRO_0000034353"
FT DOMAIN 28..145
FT /note="NTR"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00295"
FT REGION 28..31
FT /note="Involved in metalloproteinase-binding"
FT /evidence="ECO:0000250|UniProtKB:P01033"
FT REGION 93..94
FT /note="Involved in metalloproteinase-binding"
FT /evidence="ECO:0000250|UniProtKB:P01033"
FT BINDING 28
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="ligand shared with metalloproteinase partner"
FT /evidence="ECO:0000250|UniProtKB:P01033"
FT DISULFID 28..96
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00295"
FT DISULFID 30..118
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00295"
FT DISULFID 145..195
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00295"
FT DISULFID 150..155
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00295"
FT DISULFID 165..180
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00295"
FT CONFLICT 76
FT /note="S -> P (in Ref. 1; CAA08989)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 210 AA; 23980 MW; E7F4A7845CB69BD0 CRC64;
MDLRKHLGLL TLLLVAVFAF YGRPADACSC MPSHPQTHFA QADYVVQLRV LRKSDTIEPG
RTTYKVHIKR TYKATSEARR MLRDGRLSTP QDDAMCGINL DLGKVYIVAG RMPTLNICSY
YKEYTRMTIT ERHGFSGGYA KATNCTVTPC FGERCFKGRN YADTCKWSPF GKCETNYSAC
MPHKVQTVNG VISRCRWRRT QLYRKCMSNP
