GRN_CAVPO
ID GRN_CAVPO Reviewed; 605 AA.
AC P28797; H0VD49;
DT 01-DEC-1992, integrated into UniProtKB/Swiss-Prot.
DT 13-FEB-2019, sequence version 2.
DT 03-AUG-2022, entry version 88.
DE RecName: Full=Progranulin {ECO:0000250|UniProtKB:P28799};
DE Short=PGRN {ECO:0000250|UniProtKB:P28799};
DE AltName: Full=Acrogranin {ECO:0000303|PubMed:8471244};
DE AltName: Full=Proepithelin {ECO:0000250|UniProtKB:P28799};
DE Short=PEPI {ECO:0000250|UniProtKB:P28799};
DE Contains:
DE RecName: Full=Paragranulin;
DE Contains:
DE RecName: Full=Granulin-1;
DE Contains:
DE RecName: Full=Granulin-2;
DE Contains:
DE RecName: Full=Granulin-3;
DE Contains:
DE RecName: Full=Granulin-4;
DE Contains:
DE RecName: Full=Granulin-5;
DE Contains:
DE RecName: Full=Granulin-6;
DE Contains:
DE RecName: Full=Granulin-7;
DE Flags: Precursor;
GN Name=GRN;
OS Cavia porcellus (Guinea pig).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Hystricomorpha; Caviidae;
OC Cavia.
OX NCBI_TaxID=10141;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=2N;
RX PubMed=21993624; DOI=10.1038/nature10530;
RA Lindblad-Toh K., Garber M., Zuk O., Lin M.F., Parker B.J., Washietl S.,
RA Kheradpour P., Ernst J., Jordan G., Mauceli E., Ward L.D., Lowe C.B.,
RA Holloway A.K., Clamp M., Gnerre S., Alfoldi J., Beal K., Chang J.,
RA Clawson H., Cuff J., Di Palma F., Fitzgerald S., Flicek P., Guttman M.,
RA Hubisz M.J., Jaffe D.B., Jungreis I., Kent W.J., Kostka D., Lara M.,
RA Martins A.L., Massingham T., Moltke I., Raney B.J., Rasmussen M.D.,
RA Robinson J., Stark A., Vilella A.J., Wen J., Xie X., Zody M.C., Baldwin J.,
RA Bloom T., Chin C.W., Heiman D., Nicol R., Nusbaum C., Young S.,
RA Wilkinson J., Worley K.C., Kovar C.L., Muzny D.M., Gibbs R.A., Cree A.,
RA Dihn H.H., Fowler G., Jhangiani S., Joshi V., Lee S., Lewis L.R.,
RA Nazareth L.V., Okwuonu G., Santibanez J., Warren W.C., Mardis E.R.,
RA Weinstock G.M., Wilson R.K., Delehaunty K., Dooling D., Fronik C.,
RA Fulton L., Fulton B., Graves T., Minx P., Sodergren E., Birney E.,
RA Margulies E.H., Herrero J., Green E.D., Haussler D., Siepel A., Goldman N.,
RA Pollard K.S., Pedersen J.S., Lander E.S., Kellis M.;
RT "A high-resolution map of human evolutionary constraint using 29 mammals.";
RL Nature 478:476-482(2011).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 11-605, AND PROTEIN SEQUENCE OF 18-35.
RC TISSUE=Testis;
RX PubMed=8471244; DOI=10.1002/mrd.1080340302;
RA Baba T., Hoff H.B. III, Nemoto H., Lee H., Orth J., Arai Y., Gerton G.L.;
RT "Acrogranin, an acrosomal cysteine-rich glycoprotein, is the precursor of
RT the growth-modulating peptides, granulins, and epithelins, and is expressed
RT in somatic as well as male germ cells.";
RL Mol. Reprod. Dev. 34:233-243(1993).
CC -!- FUNCTION: Secreted protein that acts as a key regulator of lysosomal
CC function and as a growth factor involved in inflammation, wound healing
CC and cell proliferation (By similarity). Regulates protein trafficking
CC to lysosomes and, also the activity of lysosomal enzymes (By
CC similarity). Facilitates also the acidification of lysosomes, causing
CC degradation of mature CTSD by CTSB (By similarity). In addition,
CC functions as wound-related growth factor that acts directly on dermal
CC fibroblasts and endothelial cells to promote division, migration and
CC the formation of capillary-like tubule structures (By similarity). Also
CC promotes epithelial cell proliferation by blocking TNF-mediated
CC neutrophil activation preventing release of oxidants and proteases (By
CC similarity). Moreover, modulates inflammation in neurons by preserving
CC neurons survival, axonal outgrowth and neuronal integrity (By
CC similarity). {ECO:0000250|UniProtKB:P28798,
CC ECO:0000250|UniProtKB:P28799}.
CC -!- FUNCTION: [Granulin-3]: Inhibits epithelial cell proliferation and
CC induces epithelial cells to secrete IL-8.
CC {ECO:0000250|UniProtKB:P28799}.
CC -!- FUNCTION: [Granulin-7]: Stabilizes CTSD through interaction with CTSD
CC leading to maintain its aspartic-type peptidase activity.
CC {ECO:0000250|UniProtKB:P28799}.
CC -!- SUBUNIT: Progranulin is secreted as a homodimer. Interacts with SLPI;
CC interaction protects progranulin from proteolysis. Interacts (via
CC region corresponding to granulin-7 peptide) with CTSD; stabilizes CTSD
CC and increases its proteolytic activity. Interacts (via region
CC corresponding to granulin-7 peptide) with SORT1; this interaction
CC mediates endocytosis and lysosome delivery of progranulin; interaction
CC occurs at the neuronal cell surface in a stressed nervous system.
CC Interacts with PSAP; facilitates lysosomal delivery of progranulin from
CC the extracellular space and the biosynthetic pathway. Forms a complex
CC with PSAP and M6PR; PSAP bridges the binding between progranulin and
CC M6PR. Forms a complex with PSAP and SORT1; progranulin bridges the
CC interaction between PSAP and SORT1; facilitates lysosomal targeting of
CC PSAP via SORT1; interaction enhances PSAP uptake in primary cortical
CC neurons. Interacts (via regions corresponding to granulin-2 and
CC granulin-7 peptides) with GBA; this interaction prevents aggregation of
CC GBA-SCARB2 complex via interaction with HSPA1A upon stress. Interacts
CC (via region corresponding to granulin-7 peptide) with HSPA1A; mediates
CC recruitment of HSPA1A to GBA and prevents GBA aggregation in response
CC to stress. {ECO:0000250|UniProtKB:P28799}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:P28799}. Lysosome
CC {ECO:0000250|UniProtKB:P28799}. Note=Endocytosed by SORT1 and delivred
CC to lysosomes. Targeted to lysosome by PSAP via M6PR and LRP1, in both
CC biosynthetic and endocytic pathways (By similarity). Co-localized with
CC GBA in the intracellular trafficking compartments until to lysosome (By
CC similarity). {ECO:0000250|UniProtKB:P28798,
CC ECO:0000250|UniProtKB:P28799}.
CC -!- PTM: Cleaved by ELANE; proteolysis is blocked by SLPI and is
CC concentration- and time-dependent and induces CXCL8/IL-8 production;
CC granulin-3 and granulin-4 are resistant to ELANE. Cleaved by CTSL in
CC lysosome thus regulating the maturation and turnover of progranulin
CC within the lysosome. {ECO:0000250|UniProtKB:P28799}.
CC -!- SIMILARITY: Belongs to the granulin family. {ECO:0000305}.
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DR EMBL; AAKN02045624; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; M86735; AAA37030.1; -; mRNA.
DR PIR; I48141; I48141.
DR AlphaFoldDB; P28797; -.
DR SMR; P28797; -.
DR STRING; 10141.ENSCPOP00000007890; -.
DR Ensembl; ENSCPOT00000008867; ENSCPOP00000007890; ENSCPOG00000008789.
DR eggNOG; KOG4296; Eukaryota.
DR GeneTree; ENSGT00470000042293; -.
DR HOGENOM; CLU_026274_0_0_1; -.
DR InParanoid; P28797; -.
DR TreeFam; TF319678; -.
DR Proteomes; UP000005447; Unassembled WGS sequence.
DR Bgee; ENSCPOG00000008789; Expressed in testis and 13 other tissues.
DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0005576; C:extracellular region; ISS:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IEA:UniProtKB-KW.
DR GO; GO:0005794; C:Golgi apparatus; ISS:UniProtKB.
DR GO; GO:0005770; C:late endosome; ISS:UniProtKB.
DR GO; GO:0005765; C:lysosomal membrane; ISS:UniProtKB.
DR GO; GO:0005764; C:lysosome; ISS:UniProtKB.
DR GO; GO:0016020; C:membrane; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0005802; C:trans-Golgi network; ISS:UniProtKB.
DR GO; GO:0031982; C:vesicle; ISS:UniProtKB.
DR GO; GO:0051087; F:chaperone binding; ISS:UniProtKB.
DR GO; GO:0005125; F:cytokine activity; IEA:UniProtKB-KW.
DR GO; GO:0002265; P:astrocyte activation involved in immune response; ISS:UniProtKB.
DR GO; GO:0007042; P:lysosomal lumen acidification; ISS:UniProtKB.
DR GO; GO:0007041; P:lysosomal transport; ISS:UniProtKB.
DR GO; GO:0007040; P:lysosome organization; ISS:UniProtKB.
DR GO; GO:0002282; P:microglial cell activation involved in immune response; ISS:UniProtKB.
DR GO; GO:0050728; P:negative regulation of inflammatory response; ISS:UniProtKB.
DR GO; GO:0045824; P:negative regulation of innate immune response; ISS:UniProtKB.
DR GO; GO:1903979; P:negative regulation of microglial cell activation; ISS:UniProtKB.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; ISS:UniProtKB.
DR GO; GO:1902564; P:negative regulation of neutrophil activation; ISS:UniProtKB.
DR GO; GO:0060266; P:negative regulation of respiratory burst involved in inflammatory response; ISS:UniProtKB.
DR GO; GO:0045766; P:positive regulation of angiogenesis; ISS:UniProtKB.
DR GO; GO:1905247; P:positive regulation of aspartic-type peptidase activity; ISS:UniProtKB.
DR GO; GO:0048680; P:positive regulation of axon regeneration; ISS:UniProtKB.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; ISS:UniProtKB.
DR GO; GO:1900426; P:positive regulation of defense response to bacterium; ISS:UniProtKB.
DR GO; GO:0010595; P:positive regulation of endothelial cell migration; ISS:UniProtKB.
DR GO; GO:0050679; P:positive regulation of epithelial cell proliferation; ISS:UniProtKB.
DR GO; GO:0106016; P:positive regulation of inflammatory response to wounding; ISS:UniProtKB.
DR GO; GO:1905673; P:positive regulation of lysosome organization; ISS:UniProtKB.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; ISS:UniProtKB.
DR GO; GO:1903334; P:positive regulation of protein folding; ISS:UniProtKB.
DR GO; GO:0050821; P:protein stabilization; ISS:UniProtKB.
DR Gene3D; 2.10.25.160; -; 7.
DR InterPro; IPR000118; Granulin.
DR InterPro; IPR039036; Granulin_fam.
DR InterPro; IPR037277; Granulin_sf.
DR PANTHER; PTHR12274; PTHR12274; 1.
DR Pfam; PF00396; Granulin; 6.
DR SMART; SM00277; GRAN; 7.
DR PROSITE; PS00799; GRANULINS; 6.
PE 1: Evidence at protein level;
KW Cytokine; Direct protein sequencing; Disulfide bond; Glycoprotein;
KW Lysosome; Reference proteome; Repeat; Secreted; Signal.
FT SIGNAL 1..17
FT /evidence="ECO:0000269|PubMed:8471244"
FT CHAIN 18..605
FT /note="Progranulin"
FT /id="PRO_0000012685"
FT PEPTIDE 18..47
FT /note="Paragranulin"
FT /evidence="ECO:0000250|UniProtKB:P28799"
FT /id="PRO_0000446330"
FT PEPTIDE ?67..?112
FT /note="Granulin-1"
FT /id="PRO_0000012686"
FT PEPTIDE ?125..?178
FT /note="Granulin-2"
FT /id="PRO_0000012687"
FT PEPTIDE 220..275
FT /note="Granulin-3"
FT /id="PRO_0000012688"
FT PEPTIDE 295..349
FT /note="Granulin-4"
FT /id="PRO_0000012689"
FT PEPTIDE ?390..?429
FT /note="Granulin-5"
FT /id="PRO_0000012690"
FT PEPTIDE 453..?508
FT /note="Granulin-6"
FT /id="PRO_0000012691"
FT PEPTIDE ?532..?583
FT /note="Granulin-7"
FT /id="PRO_0000012692"
FT REGION 359..386
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 366..386
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CARBOHYD 197
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 126..139
FT /evidence="ECO:0000250|UniProtKB:P28799"
FT DISULFID 133..149
FT /evidence="ECO:0000250|UniProtKB:P28799"
FT DISULFID 297..309
FT /evidence="ECO:0000250|UniProtKB:P28799"
FT DISULFID 303..319
FT /evidence="ECO:0000250|UniProtKB:P28799"
FT DISULFID 310..327
FT /evidence="ECO:0000250|UniProtKB:P28799"
FT DISULFID 320..334
FT /evidence="ECO:0000250|UniProtKB:P28799"
FT DISULFID 328..341
FT /evidence="ECO:0000250|UniProtKB:P28799"
FT DISULFID 335..348
FT /evidence="ECO:0000250|UniProtKB:P28799"
FT DISULFID 392..404
FT /evidence="ECO:0000250|UniProtKB:P28799"
FT DISULFID 398..414
FT /evidence="ECO:0000250|UniProtKB:P28799"
FT CONFLICT 338
FT /note="G -> R (in Ref. 2; AAA37030)"
FT /evidence="ECO:0000305"
FT CONFLICT 399
FT /note="A -> R (in Ref. 2; AAA37030)"
FT /evidence="ECO:0000305"
FT CONFLICT 464
FT /note="G -> R (in Ref. 2; AAA37030)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 605 AA; 63845 MW; 22E11C38A96E5F87 CRC64;
MWTLVGWTIL VAGLVAGIRC PDDQVCPVAC CPDSGGASYS CCDPGVDLRT TALSGYLGRP
CQSPANCPIG HSCVLTAAGT AACCPFSQAM ACGDGHHCCP YGFHCSTDGG TCIQRPDIHL
LGAVQCPGGE FECPDSSTCC HMLDGSWGCC PMPQASCCED RVHCCPHGAS CDLVHIRCVT
ALGSHPLTTK LPAQRTNYTG AEGTPVVSPG LLPAALPTSV ICPDSRSQCP DDTTCCLLAS
GEYGCCPMPN AICCSDHLHC CPQDTVCDLR QSRCLSQNKA KTLLTKLPSW TVWDVECDQE
VSCPEGQTCC RLQSGKWGCC PFPKAVCCED HVHCCPEGFR CHTEKDTCEQ GLLQVPWAQK
TPAQPSRPSQ PSPPGPPGPP SPPGPLRSEI SCDEVVSCAP GNICCRLASG EWGCCPSSEG
YLCMAGERCQ VGDRLAPEKM AAHLMSLSQT TDVGCDQHAS CPVGQTCCPK LGGGWACCQL
PHAVCCEDGQ HCCPAGYTCN VKARSCEKAA DGAHLAAPLA VGSTGGVMDV ACGDRHFCHD
EQTCCRDSRG GWACCPFHQG VCCKDQRHCC PAGFHCESQG TRCVHKKSLL HWDSLPRPAA
PRPRL
