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Granulin Edit Wikipedia article
|, CLN11, GEP, GP88, PCDGF, PEPI, PGranulin, granulin precursor|
the solution structure of a well-folded peptide based on the 31-residue amino-terminal subdomain of human granulin a
|SCOPe||1pcn / SUPFAM|
Granulin is a protein that in humans is encoded by the GRN gene. Each granulin protein is cleaved from the precursor progranulin, a 593 amino acid long and 68.5 kDa protein. While the function of progranulin and granulin have yet to be determined, both forms of the protein have been implicated in development, inflammation, cell proliferation and protein homeostasis. The 2006 discovery of the GRN mutation in a population of patients with frontotemporal dementia has spurred much research in uncovering the function and involvement in disease of progranulin in the body. While there is a growing body of research on progranulin's role in the body, studies on specific granulin residues are still limited.
- 1 Progranulin
- 2 Expression
- 3 Structure
- 4 Interactive partners
- 5 Function
- 6 Clinical significance
- 7 References
- 8 Further reading
- 9 External links
Progranulin is the precursor protein for granulin. Cleavage of progranulin produces a variety of active 6 kDa granulin 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. Cleavage of progranulin into granulin occurs either in the extracellular matrix or the lysosome. Elastase, proteinase 3 and matrix metalloproteinase are proteases capable of cleaving progranulin into individual granulin peptides. Progranulin and granulin can be further differentiated by their hypothesized opposing roles in the cell. While progranulin is associated with anti-inflammation, cleaved granulin peptides have been implicated in pro-inflammatory behavior. A C. elegans study showed that granulin peptides may also participate in toxic activity.
Progranulin is expressed in a wide variety of cell types both in the periphery and in the central nervous system. Progranulin expression is low in early development, but increases as cells mature. Cell types expressing progranulin include neurons, microglia, astrocytes and endothelial cells. Progranulin has been found to be highly expressed in microglia and up-regulated during injury Within the brain, progranulin mRNA is highly expressed in pyramidal, hippocampal and Purkinje cells cells.
Each individual granulin domain peptide is 60 amino acids in length. Granulin peptides are cysteine rich and capable of forming 6 disulfide bonds per residue. The disulfide bonds form a central rod-like core that shuttles each individual granulin peptide into a stacked Î²-sheet configuration. The structure of the granulin protein is similar to the structure of proteins from protein families that consist of hormones, growth factors, ion channel modulators and enzyme inhibitors. Because of progranulin's structural similarities to these proteins, much research was done to interrogate progranulin's potential role as a growth factor. When progranulin is secreted into the extracellular matrix, it is often glycosylated at 4 confirmed and 1 tentative N-linked glycosylation sites. The n-terminus of progranulin is hypothesized to be involved in the secretion of progranulin via secretory vesicles. Specifically, Progranulin may be involved in regulating exosome excretion. The C-terminus of progranulin is hypothesized to be the primary binding partner of SORT1, a receptor of extracellular progranulin. The structural differences between each individual granulin peptide have yet to be characterized.
In the extracellular matrix, progranulin binds to receptors on several cell types resulting in either activation of a signal transduction pathway or engulfment into the cell. Several studies have shown progranulin's involvement in the binding of SORT1 and the subsequent trafficking of bounded progranulin to the lysosome. One recent study has shown that progranulin may actually mediate prosaposin trafficking to the lysosome via SORT1. However, the absence of SORT1 does not prevent exogenous progranulin from promoting neurite outgrowth or enhancing cell survival of GRN knockout cells, suggesting that other receptors are involved in mediating extracellular progranulin function For example, SORT1 -/- neuronal cells are still able to bind progranulin. Other studies have suggested tumor necrosis factor and EPH receptor A2 as potential progranulin facilitators. After binding to the receptor, progranulin may induce and modulate signaling pathways such as MAPK/ERK, PI3K/Akt, and FAK. Gene ontology enrichment analysis reveals an association between progranulin and notch receptor signaling. Granulin has also been shown to interact with Cyclin T1 and TRIB3.
Although progranulin expression increases as cells mature, they are still involved in the development of multiple cell types. Progranulin is hypothesized to be a neurotrophic factor involved in corticogenisis. Induced pluripotent stem cell lines (IPSC) harboring the GRN mutation show a decrease in cortical neuronal differentiation ability. A recent mice study suggests that progranulin may be involved in regulating the early development of cerebellar tissue by selecting for individual climbing fibers as they intersect and form synapses with Purkinje cells. In addition, several studies implicate progranulin in synaptic pruning, a microglial process that occurs during development of the neural network. Cytokines, a neuronal marker for synapse elimination, is found to be upregulated in neurons with the GRN mutation. Increased cytokine tagging results in an increase in microglial density and activity around synapses. Progranulin may also be involved in sexual determination during embryonic development.
Inflammation and wound healing
Progranulin levels are elevated when tissue is inflamed. After wounding, keratinocytes, macrophages and neutrophils increase production of progranulin. Neutrophils are capable of secreting elastase into the extracellular matrix that is capable of cleaving progranulin into granulin peptides, that promote further promote inflammation. SLPI, inhibitors of elastase, are also released by neutrophiles and macrophages to modulate progranulin cleavage. Addition of granulin B in cultured epithelial cells causes cells to secrete IL-8, a chemical that attracts monocytes and neutrophils, which further suggests the involvement of granulin peptides in promoting inflammation. The addition of exogenous SLPI and progranulin is able to alleviate the enhanced inflammatory response of mice that are unable to inhibit the cleavage of progranulin.
Progranulin is highly expressed in cells that are highly proliferative in nature. Several studies implicate progranulin in tumorigenesis and neuronal outgrowth. Progranulin promotes mitogenesis in epithelial cultures. When two epithelial lines were cultured in media with recombinant PGRN, proliferation was stimulated. Knockout of both progranulin homologues in a zebrafish model reduces axonal outgrowth. In primary cortical and motor neurons, progranulin regulates neuronal outgrowth and survival. In primary motor neurons, progranulin has been shown to increase neurite outgrowth by regulating the glycogen synthase kinase-3 beta. Progranulin may function as an autocrine growth factor in tumorigenesis.
The discovery of a GRN mutation leading to lysosomal storage disorder led to many studies that explored progranulin's role in regulating protein homeostasis via the lysosomal pathway. Transcriptional gene network interference study suggests that progranulin is highly involved in lysosomal function and organization. Imaging studies have shown co-localization of progranulin and lysosomal marker LAMP-1. Progranulin expression is regulated by TFEB, a transcription factor that mediates proteins involved in lysosomal biosynthesis. Progranulin may be involved in regulating protease activity. Proteases that could be regulated by progranulin include prosaposin, which is cleaved into saposin peptides in the lysosome, and cathepsin D, the primary protease involved in protein aggregate break down. GRN mutation shares similar neuropathology and clinical phenotype with CHMP2B and VCP mutations, genes that are both involved in the trafficking and breakdown of proteins involved in lysosomal function.
Frontal temporal dementia
Heterozygous mutation of the GRN gene leading to progranulin haploinsufficiency causes Frontal Temporal Dementia.  These mutations include frameshift, splice site, nonsense signal peptide, Kozak sequence disruptions and missense mutations, which result in either nonsense-mediated decay or the production of non-functional protein. Patients with GRN caused FTD (GRN-FTD) exhibit asymmetric brain atrophy, although age of onset, disease progression and clinical symptoms vary, suggesting that other genetic or environmental factors may be involved in disease expression. Pathological indicators include cytosolic ubiquitin deposits enriched in hyperphosphorylated TAR DNA Binding Protein (TDP-43), autophagy-related protein aggregates, ubiquitin-binding protein p62, lentiform intranuclear inclusions, dystrophic neurites and inflammation. Patients with the heterozygote mutation exhibit a reduction of 70-80% serum progranulin levels when compared to controls. Reprogrammed stem cells restore GRN mRNA levels to 50%, further suggesting that some other genetic or environmental factor is involved in regulating FTD disease expression. Mice exhibit reduced autophagic flux and autophagy-dependent clearance. Human FTLD-GRN derived fibroblasts show decrease lysosomal protease activity and lymphoblasts containing neuronal ceroid lipofuscinosis-like storage material. FTLD-GRN IPSC cortical Neurons have enlarged vesicles, lipofuscin accumulation and cathepsin D deficiency.
Neuronal ceroid lipofuscinosis
Homozygous mutation of the GRN gene causes neuronal ceroid lipofuscinosis (NCL) characterized by an accumulation of autofluorescent lipofuscin, enlarged vacuoles, impairment in lysosomal activity, retinal & brain degeneration, exaggerated inflammatory responses, microgliosis, astrogliosis and behavioral dysfunction such as OCD-like and disinhibition-like behavior. Aged GRN double mutant mice have lipofuscin deposits and enlarge lysosomes, while one group found phosphorylated TDP-43.
Progranulin may also be involved in cancer development, atherosclerosis and metabolic disease. Progranulin can promote cyclin D1 expression in breast cancer lines and phosphorylation of proteins through extracellular regulated kinase signaling pathways. Progranulin is highly expressed in ovarian, adrenal carcinomas and immortalized epithelial cells. There is a correlation between Progranulin concentration and cancer severity. Granulin release by macrophages has been associated with fibrotic hepatic metastasis in pancreatic cancer. The human liver fluke (Opisthorchis viverrini) contributes to the development of bile duct (liver) cancer by secreting a granulin-like growth hormone. Progranulin may also be involved in promoting the progression of atherosclerosis. While progranulin may be anti-atherogenic, granulins may be pro-atherogenic. Increased serum and plasma progranulin levels in patients with type 2 diabetes and visceral obesity implicating progranulin in metabolic diseases.
- GRCh38: Ensembl release 89: ENSG00000030582 - Ensembl, May 2017
- GRCm38: Ensembl release 89: ENSMUSG00000034708 - Ensembl, May 2017
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- Zhou Y, Li L, Liu Q, Xing G, Kuai X, Sun J, et al. (May 2008). "E3 ubiquitin ligase SIAH1 mediates ubiquitination and degradation of TRB3". Cellular Signalling. 20 (5): 942â€“8. doi:10.1016/j.cellsig.2008.01.010. PMID 18276110.
- Raitano S, OrdovÃ s L, De Muynck L, Guo W, Espuny-Camacho I, Geraerts M, et al. (January 2015). "Restoration of progranulin expression rescues cortical neuron generation in an induced pluripotent stem cell model of frontotemporal dementia". Stem Cell Reports. 4 (1): 16â€“24. doi:10.1016/j.stemcr.2014.12.001. PMC 4297877. PMID 25556567.
- Uesaka N, Abe M, Konno K, Yamazaki M, Sakoori K, Watanabe T, et al. (February 2018). "Retrograde Signaling from Progranulin to Sort1 Counteracts Synapse Elimination in the Developing Cerebellum". Neuron. 97 (4): 796â€“805.e5. doi:10.1016/j.neuron.2018.01.018. PMID 29398357.
- Lui H, Zhang J, Makinson SR, Cahill MK, Kelley KW, Huang HY, et al. (May 2016). "Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation". Cell. 165 (4): 921â€“35. doi:10.1016/j.cell.2016.04.001. PMC 4860138. PMID 27114033.
- GÃ¶tzl JK, Lang CM, Haass C, Capell A (December 2016). "Impaired protein degradation in FTLD and related disorders". Ageing Research Reviews. 32: 122â€“139. doi:10.1016/j.arr.2016.04.008. PMID 27166223.
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- Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, et al. (August 2006). "Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17". Nature. 442 (7105): 916â€“9. Bibcode:2006Natur.442..916B. doi:10.1038/nature05016. PMID 16862116.
- Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, et al. (August 2006). "Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21". Nature. 442 (7105): 920â€“4. Bibcode:2006Natur.442..920C. doi:10.1038/nature05017. PMID 16862115.
- Nielsen SR, Quaranta V, Linford A, Emeagi P, Rainer C, Santos A, et al. (May 2016). "Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis". Nature Cell Biology. 18 (5): 549â€“60. doi:10.1038/ncb3340. PMC 4894551. PMID 27088855.
- Smout MJ, Laha T, Mulvenna J, Sripa B, Suttiprapa S, Jones A, et al. (October 2009). "A granulin-like growth factor secreted by the carcinogenic liver fluke, Opisthorchis viverrini, promotes proliferation of host cells". PLoS Pathogens. 5 (10): e1000611. doi:10.1371/journal.ppat.1000611. PMC 2749447. PMID 19816559.
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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.
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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 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).
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|Number in seed:||290|
|Number in full:||3774|
|Average length of the domain:||42.60 aa|
|Average identity of full alignment:||48 %|
|Average coverage of the sequence by the domain:||25.89 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 47079205 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||19|
|Download:||download the raw HMM for this family|
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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 13 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 sequence.
Loading structure mapping...