Summary: Granulin
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Granulin Edit Wikipedia article
| Granulin | |||||||||
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| the solution structure of a well-folded peptide based on the 31-residue amino-terminal subdomain of human granulin a | |||||||||
| Identifiers | |||||||||
| Symbol | Granulin | ||||||||
| Pfam | PF00396 | ||||||||
| InterPro | IPR000118 | ||||||||
| PROSITE | PDOC00634 | ||||||||
| SCOP | 1pcn | ||||||||
| SUPERFAMILY | 1pcn | ||||||||
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Granulin is a protein that in humans is encoded by the GRN gene.[1][2][3]
Contents |
[edit] Structure
Granulins are a family of secreted, glycosylated peptides that are cleaved from a single precursor protein with 7.5 repeats of a highly conserved 12-cysteine granulin/epithelin motif. The 88 kDa precursor protein, progranulin, is also called proepithelin and PC cell-derived growth factor. Cleavage of the signal peptide produces mature granulin which can be further cleaved into a variety of active, 6 kDa peptides. These smaller cleavage products are named granulin A, granulin B, granulin C, etc. Epithelins 1 and 2 are synonymous with granulins A and B, respectively.
[edit] Function
Both the peptides and intact granulin protein regulate cell growth. However, different members of the granulin protein family may act as inhibitors, stimulators, or have dual actions on cell growth. Granulin family members are important in normal development, wound healing, and tumorigenesis.[3]
[edit] Clinical significance
The human liver fluke (Opisthorchis viverrini) contributes to the development of bile duct (liver) cancer by secreting a granulin-like growth hormone.[4]
Mutations in the GRN gene have been implicated in up to 25% of frontotemporal lobar degeneration, inherited in an autosomal dominant fashion with high penetrance.[5] Several loss-of-function mutations disease-causing mutations in GRN have been identified.[6][7]
[edit] Interactions
Granulin has been shown to interact with Cyclin T1[8] and TRIB3.[9]
[edit] References
- ^ Bhandari V, Bateman A (Nov 1992). "Structure and chromosomal location of the human granulin gene". Biochem Biophys Res Commun 188 (1): 57–63. doi:10.1016/0006-291X(92)92349-3. PMID 1417868.
- ^ Zhang H, Serrero G (Dec 1998). "Inhibition of tumorigenicity of the teratoma PC cell line by transfection with antisense cDNA for PC cell-derived growth factor (PCDGF, epithelin/granulin precursor)". Proc Natl Acad Sci U S A 95 (24): 14202–7. Bibcode 1998PNAS...9514202Z. doi:10.1073/pnas.95.24.14202. PMC 24351. PMID 9826678. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=24351.
- ^ a b "Entrez Gene: GRN granulin". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2896.
- ^ Smout MJ, Laha T, Mulvenna J, Sripa B, Suttiprapa S, Jones A, Brindley PJ, Loukas A (October 2009). "A granulin-like growth factor secreted by the carcinogenic liver fluke, Opisthorchis viverrini, promotes proliferation of host cells". PLoS Pathog. 5 (10): e1000611. doi:10.1371/journal.ppat.1000611. PMC 2749447. PMID 19816559. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2749447.
- ^ MacKenzie, I. R. A. (2007). "The neuropathology and clinical phenotype of FTD with progranulin mutations". Acta Neuropathologica 114 (1): 49–40. doi:10.1007/s00401-007-0223-8. PMID 17458552.
- ^ Baker, M.; MacKenzie, I. R.; Pickering-Brown, S. M.; Gass, J.; Rademakers, R.; Lindholm, C.; Snowden, J.; Adamson, J. et al. (2006). "Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17". Nature 442 (7105): 916. Bibcode 2006Natur.442..916B. doi:10.1038/nature05016. PMID 16862116.
- ^ Cruts, M.; Gijselinck, I.; Van Der Zee, J.; Engelborghs, S.; Wils, H.; Pirici, D.; Rademakers, R.; Vandenberghe, R. et al. (2006). "Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21". Nature 442 (7105): 920. Bibcode 2006Natur.442..920C. doi:10.1038/nature05017. PMID 16862115.
- ^ Hoque M, Young TM, Lee CG, Serrero G, Mathews MB, Pe'ery T (March 2003). "The growth factor granulin interacts with cyclin T1 and modulates P-TEFb-dependent transcription". Mol. Cell. Biol. 23 (5): 1688–702. doi:10.1128/MCB.23.5.1688-1702.2003. PMC 151712. PMID 12588988. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=151712.
- ^ Zhou Y, Li L, Liu Q, Xing G, Kuai X, Sun J, Yin X, Wang J, Zhang L, He F (May 2008). "E3 ubiquitin ligase SIAH1 mediates ubiquitination and degradation of TRB3". Cell. Signal. 20 (5): 942–8. doi:10.1016/j.cellsig.2008.01.010. PMID 18276110.
[edit] Further reading
- Eriksen J, Mackenzie IR (2008). "Progranulin: normal function and role in neurodegeneration.". J Neurochem 104 (2): 287–297. doi:10.1111/j.14714159.2007.04968.x. PMID 117953663.
- Serrero G (2003). "Autocrine growth factor revisited: PC-cell-derived growth factor (progranulin), a critical player in breast cancer tumorigenesis.". Biochem. Biophys. Res. Commun. 308 (3): 409–13. doi:10.1016/S0006-291X(03)01452-9. PMID 12914763.
- Ahmed Z, Mackenzie IR, Hutton ML, Dickson DW (2007). "Progranulin in frontotemporal lobar degeneration and neuroinflammation.". Journal of neuroinflammation 4: 7. doi:10.1186/1742-2094-4-7. PMC 1805428. PMID 17291356. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1805428.
- Mackenzie IR (2007). "The neuropathology and clinical phenotype of FTD with progranulin mutations.". Acta Neuropathol. 114 (1): 49–54. doi:10.1007/s00401-007-0223-8. PMID 17458552.
- Pickering-Brown SM (2007). "Progranulin and frontotemporal lobar degeneration.". Acta Neuropathol. 114 (1): 39–47. doi:10.1007/s00401-007-0241-6. PMID 17572900.
- Bhandari V, Palfree RG, Bateman A (1992). "Isolation and sequence of the granulin precursor cDNA from human bone marrow reveals tandem cysteine-rich granulin domains.". Proc. Natl. Acad. Sci. U.S.A. 89 (5): 1715–9. Bibcode 1992PNAS...89.1715B. doi:10.1073/pnas.89.5.1715. PMC 48523. PMID 1542665. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=48523.
- Plowman GD, Green JM, Neubauer MG, et al. (1992). "The epithelin precursor encodes two proteins with opposing activities on epithelial cell growth.". J. Biol. Chem. 267 (18): 13073–8. PMID 1618805.
- Bateman A, Belcourt D, Bennett H, et al. (1991). "Granulins, a novel class of peptide from leukocytes.". Biochem. Biophys. Res. Commun. 173 (3): 1161–8. doi:10.1016/S0006-291X(05)80908-8. PMID 2268320.
- Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides.". Gene 138 (1-2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
- Baba T, Hoff HB, Nemoto H, et al. (1993). "Acrogranin, an acrosomal cysteine-rich glycoprotein, is the precursor of the growth-modulating peptides, granulins, and epithelins, and is expressed in somatic as well as male germ cells.". Mol. Reprod. Dev. 34 (3): 233–43. doi:10.1002/mrd.1080340302. PMID 8471244.
- Kardana A, Bagshawe KD, Coles B, et al. (1993). "Characterisation of UGP and its relationship with beta-core fragment.". Br. J. Cancer 67 (4): 686–92. doi:10.1038/bjc.1993.127. PMC 1968365. PMID 8471426. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1968365.
- Zhou J, Gao G, Crabb JW, Serrero G (1993). "Purification of an autocrine growth factor homologous with mouse epithelin precursor from a highly tumorigenic cell line.". J. Biol. Chem. 268 (15): 10863–9. PMID 8496151.
- Andersson B, Wentland MA, Ricafrente JY, et al. (1996). "A "double adaptor" method for improved shotgun library construction.". Anal. Biochem. 236 (1): 107–13. doi:10.1006/abio.1996.0138. PMID 8619474.
- Bhandari V, Daniel R, Lim PS, Bateman A (1996). "Structural and functional analysis of a promoter of the human granulin/epithelin gene.". Biochem. J. 319 (2): 441–7. PMC 1217788. PMID 8912679. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1217788.
- Yu W, Andersson B, Worley KC, et al. (1997). "Large-scale concatenation cDNA sequencing.". Genome Res. 7 (4): 353–8. doi:10.1101/gr.7.4.353. PMC 139146. PMID 9110174. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=139146.
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, et al. (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library.". Gene 200 (1-2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
- Trinh DP, Brown KM, Jeang KT (1999). "Epithelin/granulin growth factors: extracellular cofactors for HIV-1 and HIV-2 Tat proteins.". Biochem. Biophys. Res. Commun. 256 (2): 299–306. doi:10.1006/bbrc.1999.0317. PMID 10079180.
- He Z, Bateman A (1999). "Progranulin gene expression regulates epithelial cell growth and promotes tumor growth in vivo.". Cancer Res. 59 (13): 3222–9. PMID 10397269.
- Thornton MA, Poncz M, Korostishevsky M, et al. (1999). "The human platelet alphaIIb gene is not closely linked to its integrin partner beta3.". Blood 94 (6): 2039–47. PMID 10477733.
[edit] External links
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This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Granulin Provide feedback
No Pfam abstract.
Internal database links
| SCOOP: | FYRN |
External database links
| PANDIT: | PF00396 |
| PROSITE: | PDOC00634 |
| Pseudofam: | PF00396 |
| SCOP: | 1pcn |
| SYSTERS: | Granulin |
This tab holds annotation information from the InterPro database.
InterPro entry IPR000118
Metazoan granulins [PUBMED:1542665] are a family of cysteine-rich peptides of about 6 Kd which may have multiple biological activity. A precursor protein (known as acrogranin) potentially encodes seven different forms of granulin (grnA to grnG) which are probably released by post-translational proteolytic processing. Granulins are evolutionary related to a PMP-D1, a peptide extracted from the pars intercerebralis of migratory locusts [PUBMED:1740125]. A schematic representation of the structure of a granulin is shown below:
xxxCxxxxxCxxxxxCCxxxxxxxxCCxxxxxxCCxxxxxCCxxxxxCxxxxxxCx
'C': conserved cysteine probably involved in a disulphide bond.
In plants a granulin domain is often associated with the C terminus of cysteine proteases belong to the MEROPS peptidase family C1, subfamily C1A (papain).
Domain organisation
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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Alignments
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...
View options
We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
| Seed (94) |
Full (1181) |
Representative proteomes | NCBI (1067) |
Meta (2) |
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| RP15 (196) |
RP35 (261) |
RP55 (377) |
RP75 (509) |
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| Jalview | ||||||||
| HTML | ||||||||
| PP/heatmap | 1 | |||||||
| Pfam viewer | ||||||||
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
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Format an alignment
Download options
We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
| Seed (94) |
Full (1181) |
Representative proteomes | NCBI (1067) |
Meta (2) |
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|---|---|---|---|---|---|---|---|---|
| RP15 (196) |
RP35 (261) |
RP55 (377) |
RP75 (509) |
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| Raw Stockholm | ||||||||
| Gzipped | ||||||||
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
External links
MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.
HMM logo
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
Trees
This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
Curation
| Seed source: | Prosite |
| Previous IDs: | granulin; |
| Type: | Family |
| Author: | Finn RD |
| Number in seed: | 94 |
| Number in full: | 1181 |
| Average length of the domain: | 43.50 aa |
| Average identity of full alignment: | 48 % |
| Average coverage of the sequence by the domain: | 31.13 % |
HMM information
| HMM build commands: |
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
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| Model details: |
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| Model length: | 43 | ||||||||||||
| Family (HMM) version: | 13 | ||||||||||||
| Download: | download the raw HMM for this family |
Species distribution
Sunburst controls
ShowThis visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...
Tree controls
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Structures
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Granulin domain has been found. There are 9 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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Archea
Eukaryota
Bacteria
Other sequences
Viruses
Unclassified
Viroids
Unclassified sequence