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This is the Wikipedia entry entitled "Granulin". More...
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Granulin Edit Wikipedia article
Solution structure of the N-terminal sub-domain of human granulin A based on PDB 1g26.
|RNA expression pattern|
|the solution structure of a well-folded peptide based on the 31-residue amino-terminal subdomain of human granulin a|
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.
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.
 Clinical significance
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. Several loss-of-function mutations disease-causing mutations in GRN have been identified.
- 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.
- "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.
 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.
|This article on a gene on chromosome 17 is a stub. You can help Wikipedia by expanding it.|
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
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Internal database links
External database links
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).
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
Finally, because some families can be found in a very large number of architectures, we load only the first fifty architectures by default. If you want to see more architectures, click the button at the bottom of the page to load the next set.
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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...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the NCBI sequence database using the family HMM
- alignment generated by searching the metagenomics sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- a Java applet developed at the University of Dundee. You will need Java installed before running jalview
- an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
- an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
- Pfam viewer
- an HTML-based viewer that uses DAS to retrieve alignment fragments on request
You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.
You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.
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.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
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.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
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 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...
If you find these logos useful in your own work, please consider citing the following article:
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.
|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 build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||13|
|Download:||download the raw HMM for this family|
Weight segments by...
Change the size of the sunburst
selected sequences to HMM
a FASTA-format file
- 0 sequences
- 0 species
This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
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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