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2  structures 195  species 0  interactions 230  sequences 10  architectures

Family: Folliculin_C (PF16692)

Summary: Folliculin C-terminal domain

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

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Folliculin Edit Wikipedia article

FLCN
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases FLCN, BHD, FLCL, Folliculin
External IDs MGI: 2442184 HomoloGene: 14583 GeneCards: FLCN
Gene location (Human)
Chromosome 17 (human)
Chr. Chromosome 17 (human)[1]
Chromosome 17 (human)
Genomic location for FLCN
Genomic location for FLCN
Band 17p11.2 Start 17,212,212 bp[1]
End 17,237,188 bp[1]
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_144606
NM_144997
NM_001353229
NM_001353230
NM_001353231

NM_001271356
NM_001271357
NM_146018

RefSeq (protein)

NP_653207
NP_659434
NP_001340158
NP_001340159
NP_001340160

NP_001258285
NP_001258286
NP_666130

Location (UCSC) Chr 17: 17.21 – 17.24 Mb Chr 17: 59.79 – 59.81 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Folliculin also known as FLCN, Birt-Hogg-Dubé syndrome protein or FLCN_HUMAN is a protein that in humans is associated with Birt-Hogg-Dubé syndrome and hereditary spontaneous pneumothorax. It is encoded by the Folliculin (FLCN) gene (alias BHD, FLCL) that acts as a tumor suppressor gene. Tumor suppressors help control the growth and division of cells.[5]

Gene

Structure

The FLCN gene consists of 14 exons.[6]

Location

Cytogenetic Location: The FLCN gene is located on the short (p) arm of chromosome 17 at position 11.2. (17p11.2).[5]

Molecular Location on chromosome 17: base pairs 17,056,252 to 17,081,230 (NCI Build 36.1)

Clinical Significance

Germline mutations in the FLCN gene cause Birt-Hogg-Dubé syndrome (BHD), an autosomal dominant disease that predisposes individuals to develop benign tumors of the hair follicle called fibrofolliculomas, lung cysts, spontaneous pneumothorax, and an increased risk for kidney tumors.[6] FLCN mutations have also been found in the germline of patients with inherited spontaneous pneumothorax and no other clinical manifestations.[7] [8]

In a risk assessment performed in affected and unaffected members of BHD families, the odds ratio for developing kidney tumors in a person affected with BHD was 6.9 times greater than his unaffected siblings. The odds ratio for spontaneous pneumothorax in BHD affected individuals, when adjusted for age, was 50.3 times greater than unaffected family members.[9]

Discovery

Birt-Hogg-Dubé syndrome was originally described by three Canadian physicians in a family in which 15 of 70 members over 3 generations exhibited a triad of dermatological lesions (fibrofolliculomas, trichodiscomas and acrochordons).[10] Subsequently, cosegregation of kidney neoplasms with BHD cutaneous lesions was observed in 3 families with a family history of kidney tumors,[11] suggesting that kidney tumors may be part of the BHD syndrome phenotype. In order to identify the genetic locus for BHD syndrome, genetic linkage analysis was performed in families recruited on the basis of BHD cutaneous lesions.[12] [13] A region spanning chromosome 17p11 was identified and mutations in a novel gene, FLCN, were subsequently found in the germline of individuals affected with BHD syndrome.[6]

Genetics

The FLCN gene encodes a novel 64 kDa protein, FLCN, which is highly conserved across species. The majority of germline FLCN mutations identified in BHD patients are loss-of-function mutations including frameshift mutations (insertion/deletion), nonsense mutations, and splice site mutations that are predicted to inactivate the FLCN protein, although some missense mutations have been reported that exchange one nucleotide for another and consequently result in a different amino acid at the mutation site.[14] Most mutations are identified by DNA sequencing. With the advent of multiplex ligation-dependent probe amplification (MLPA) technology, partial deletions of the FLCN gene have also been identified [15] [16]permitting a FLCN mutation detection rate in BHD cohorts that approaches 90%.[14] Very few FLCN mutations have been found in association with sporadic kidney tumors indicating that FLCN mutation may play only a minor role in non-inherited kidney cancer.[17][18][19]

Experimental evidence supports a role for FLCN as a tumor suppressor gene. In BHD-associated kidney tumors, the inherited FLCN gene with a germline mutation is present in all cells, but the remaining wild type copy is inactivated in the tumor cells through somatic mutation or loss of heterozygosity.[20] Naturally-occurring dog and rat models with germline Flcn mutations develop kidney tumors that retain only the mutant copy of the gene.[21][22] Homozygous inactivation of Flcn in these animal models is lethal to the embryo. Tumors develop in mice injected with FLCN-deficient kidney cancer cells from BHD-associated human tumors but when wild type FLCN is restored in these cells, tumor development is inhibited.[23] Additionally, injection of kidney tumor cells from the adenocarcinoma cell line ACHN with FLCN inactivation into immunocompromised mice resulted in the growth of significantly larger tumors, further underscoring a tumor suppressor role for FLCN.[24] Based on the presence of FLCN staining by immunohistochemistry, haploinsufficiency, that is mutation of one copy of FLCN with retention of the wild type copy, may be sufficient for the development of fibrofolliculomas [25]and lung cysts.[26]

Function

Interactions

FLCN has been shown to interact through its C-terminus with two novel proteins, folliculin interacting protein 1 (FNIP1)[27] and folliculin interacting protein 2 (FNIP2/FNIPL)[28] [29], and indirectly through FNIP1 and FNIP2 with AMP-activated protein kinase (AMPK).[27][28] AMPK is an important energy sensor in cells and negative regulator of mechanistic target of rapamycin (mTOR) [30] suggesting that FLCN and FNIP1 may play a role in modulating mTOR activity through energy or nutrient sensing pathways. Coimmunoprecipitation experiments with FNIP1 and FLCN expressed in HEK293 cells and in vitro binding assays have shown that the C-terminus of FLCN and amino acids 300 to 1166 of FNIP1 are required for optimal FLCN-FNIP1 binding.[27] FLCN and FNIP1 colocalized to the cytoplasm in a reticular pattern.

FLCN phosphorylation

FLCN phosphorylation was diminished by rapamycin and amino acid starvation and facilitated by FNIP1 overexpression, suggesting that FLCN phosphorylation may be regulated by mTOR and AMPK signaling. FNIP1 was phosphorylated by AMPK and its phosphorylation was inhibited in a dose-dependent manner by an AMPK inhibitor, resulting in reduced FNIP1 expression.[27] FLCN has multiple phosphorylation sites including serine 62, which are differentially affected by FNIP1 binding and by inhibitors of mTOR and AMPK.[27][31] The significance of this modification, however, is unknown.

Proposed functions of FLCN

Several pathways in which FLCN plays a role as a tumor suppressor have been identified, but it remains to be determined which of these pathways when dysregulated leads to the cutaneous, lung and kidney phenotypes associated with Birt-Hogg-Dubé syndrome.

Regulation of the AKT-mTOR pathway

Work with Flcn-deficient mouse models suggests a role for FLCN in regulating the AKT-mechanistic target of rapamycin (mTOR) signaling pathway, but the results are conflicting. mTOR activation was seen in the highly cystic kidneys that developed in mice with kidney-targeted inactivation of Flcn.[32] [33] Elevated AKT and phospho-AKT proteins, and activation of mTORC1 and mTORC2 were observed in late-onset tumors that developed in aged Flcn heterozygous mice subsequent to loss of the remaining Flcn wild type allele, and in FLCN-deficient kidney tumors from BHD patients.[34] On the other hand, mTOR inhibition was demonstrated in smaller cysts (although mTOR activation was seen in larger cysts) that developed in Flcn heterozygous knockout mice generated with a gene trapping approach.[24] N-ethyl-N-nitrosourea (ENU) mutagenesis of another Flcn heterozygous mouse model produced tumors with reduced mTOR activity.[35] Evidence from studies in yeast suggests that the FLCN ortholog Bhd activates the mTOR ortholog Tor2.[36] These opposing effects of FLCN deficiency on the mTOR pathway have led to the hypothesis that FLCN regulation of mTOR activity may be context or cell-type dependent.

mTORC1 activation on the lysosome

Resolution of the crystal structure of the FLCN carboxy-terminal protein domain revealed a structural similarity to the differentially expressed in normal cells and neoplasia (DENN) domain of DENN1B suggesting that they are distantly related proteins. The DENN domain family of proteins are guanine nucleotide exchange factors (GEFs) for Rab proteins, members of the Ras superfamily of G proteins that are involved in vesicular transport suggesting that FLCN may have a similar function.[37]

FLCN acts as a GTPase-activating protein (GAP) toward Rag C/D GTPases, members of another Ras-related GTP-binding protein family, which are necessary for amino acid-dependent mTORC1 activation at the lysosomal membrane.[38] The heterodimeric Rag GTPases (RagA or B in complex with RagC or D) in a lysosome-associated complex with Ragulator and vacuolar adenosine triphosphatase (v-ATPase) interact with mTORC1 in response to amino acids from the lysosomal lumen to promote translocation of mTORC1 to the lysosomal surface for activation by the small GTPase Ras-homolog enriched in brain (Rheb). GTP-loading of RagA/B is a requirement for amino acid signaling to mTORC1.[39] In recent studies, FLCN was shown to localize to the lysosome surface under amino acid starved conditions, where with its binding partners FNIP1/FNIP2, FLCN acts as a GAP to facilitate GDP-loading of Rag C/D, clarifying the role of this Rag GTPase in amino acid-dependent mTORC1 activation.[38] Another report demonstrated that FLCN in association with FNIP1 preferentially binds to GDP-bound /nucleotide free Rag A/B under amino acid deprived conditions suggesting a potential role for FLCN as a GEF for RagA/B.[40] Recently the heterodimeric Lst4-Lst7 complex in yeast, orthologous to the mammalian FLCN-FNIP1 complex, was found to function as a GAP for Gtr2, the yeast ortholog of Rag C/D, and cluster at the vacuolar membrane in amino acid starved cells. Refeeding of amino acids stimulated Lst4-Lst7 binding to and GAP activity towards Gtr2 resulting in mTORC1 activation and demonstrating conservation of a GAP function for FLCN in lower organisms. [41]

Control of TFE3/TFEB transcriptional activation

TFE3 and TFEB are members of the microphthalmia-associated transcription factor (MiTF) family, which also includes MiTF and TFEC. Gene fusions of TFE3 with a number of different gene partners can arise sporadically and are responsible for Xp11.2 translocation renal cell carcinoma.[42] FLCN-deficient BHD associated renal tumors and tumors that develop in mouse models with Flcn inactivation were found to have elevated expression of transmembrane glycoprotein NMB (GPNMB), a transcriptional target of TFE3.[43] Subsequently, FLCN was shown to regulate TFE3 activity by sequestering TFE3 in the cytoplasm where it is transcriptionally inactive; however, loss of FLCN expression results in localization of TFE3 to the nucleus driving transcriptional activation of its target genes including GPNMB.[43] Another study investigating genes required for mouse embryonic stem cell (ESC) progression from pluripotency to cell lineage differentiation revealed that Flcn in complex with Fnip1/2 was necessary for ESC exit from pluripotency through cytoplasmic sequestering of Tfe3, thereby abrogating expression of its gene target, estrogen-related receptor beta(Esrrb), the core pluripotency factor.[44]

Regulation of PGC-1α and mitochondrial biogenesis

Chromophobe renal carcinoma and hybrid oncocytic tumors with features of chromophobe renal carcinoma and renal oncocytoma, which are the most common renal tumor histologic subtypes associated with BHD, contain large numbers of mitochondria. Comparative gene expression profiling of BHD-associated renal tumors and sporadic counterpart tumors revealed distinct gene expression patterns and cytogenetic differences between the groups. BHD-associated tumors displayed high expression of mitochondrial- and oxidative phosphorylation-associated genes reflecting deregulation of the peroxisome proliferator-activated receptor gamma coactivator 1-alpha / mitochondrial transcription factor A (PGC-1α/TFAM) signaling axis.[45] FLCN expression was inversely correlated with PGC-1α activation, which drives mitochondrial biogenesis. In support of these data, FLCN inactivation was correlated with PGC-1α activation and upregulation of its target genes in BHD-associated renal tumors, and kidney, heart and muscle tissues from genetically engineered mouse models with Flcn inactivation targeted to the respective tissues.[46][47]

Maintenance of cell-cell adhesions and regulation of RhoA signaling

Yeast two-hybrid screening performed by two independent groups identified p0071 (plakophilin-4) as a FLCN interacting protein.[48][49] p0071 binds E-cadherin at adherens junctions, which are important for maintenance of cell architecture in epithelial tissues, and regulates RhoA activity. Loss of FLCN function leads to a disruptive effect on cell-cell adhesions and cell polarity, and dysregulation of RhoA signaling. Additional supporting evidence includes reduction in E-cadherin expression and increased alveolar apoptosis in lungs from lung-targeted Flcn-deficient mice[50], and increased cell-cell adhesions in FLCN-deficient lung cell lines.[51] These studies suggest a potential function of FLCN in maintaining proper cell-cell adhesions for lung cell integrity and support the “stretch hypothesis” as a mechanism of pulmonary cyst pathogenesis in BHD.[52]

Ciliogenesis and cilia-dependent flow sensory mechanisms

Individuals affected with the inherited kidney cancer syndromes von Hippel-Lindau syndrome and tuberous sclerosis complex can develop kidney cysts in addition to kidney tumors, which have been shown to result from defects in primary cilia function.[53] [54]BHD patients also may present with kidney cysts, which led researchers to investigate a potential role for FLCN in regulating primary cilia development and/or function. FLCN protein was found to localize on primary cilia, the basal body and centrosome in different cell types. FLCN siRNA knockdown in nutrient starved kidney cells resulted in delayed cilia development. Both overexpression of FLCN in FLCN-expressing kidney cells and knockdown of FLCN resulted in reduced numbers of cilia and aberrant cell divisions, suggesting that levels of FLCN must be tightly regulated for proper ciliogenesis. [55]Primary cilia play a role in inhibiting the canonical Wnt signaling pathway ( Wnt/β-catenin signaling pathway) by sequestering β-catenin in the basal body, and dysregulated Wnt/β-catenin signaling has been linked to kidney cyst formation. In Flcn-deficient mouse inner medullary collecting duct cells, levels of unphosphorylated (active) β-catenin and its down stream targets were elevated suggesting that improper activation of the canonical Wnt/β-catenin signaling pathway through defective ciliogenesis may lead to kidney, and potentially lung, cyst development in BHD syndrome.[55]

Additional experimental evidence that FLCN may be involved in primary cilium function was obtained from a yeast two-hybrid screening that identified KIF3A as a FLCN interacting protein.[56] Intraflagellar transport, which is required for primary cilium assembly and maintenance, is driven by kinesin-2 motor made up of subunits KIF3A and KIF3B. Researchers have shown that FLCN could interact with both subunits in a cilium-dependent manner and localize to cilia in FLCN-expressing but not FLCN-deficient cells.[56] Cilia have been shown to act as flow sensors and suppress mTOR signaling by activating the serine/threonine kinase LKB1 located in the basal body of resting cells in response to flow stimuli. LKB1 in turn phosphorylates and activates AMPK, a negative regulator of mTOR activation.[57] Flow stress was able to suppress mTOR signaling in FLCN-expressing human kidney cells but not under FLCN deficient conditions, and required intact cilia. FLCN was shown to recruit LKB1 and facilitate its interaction with AMPK in the basal body in a flow stress-dependent manner.[56] These findings suggest a role for FLCN in the mechanosensory signaling machinery of the cell that controls the cilia-dependent regulation of the LKB1-AMPK-mTOR signaling axis.

Other potential functions of FLCN

Additional potential roles for FLCN in autophagy, [58] [59] [60] TGF β signaling,[61] [23] regulation of AMPK activity, [58][62] [63] and regulation of HIF-1α transcriptional activity [64] [62]have been described.

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  44. ^ Betschinger J, Nichols J, Dietmann S, Corrin PD, Paddison PJ, Smith A (April 2013). "Exit from pluripotency is gated by intracellular redistribution of the bHLH transcription factor Tfe3". Cell. 153 (2): 335–47. doi:10.1016/j.cell.2013.03.012. PMID 23582324. 
  45. ^ Klomp JA, Petillo D, Niemi NM, Dykema KJ, Chen J, Yang XJ, et al. (December 2010). "Birt-Hogg-Dubé renal tumors are genetically distinct from other renal neoplasias and are associated with up-regulation of mitochondrial gene expression". BMC Medical Genomics. 3: 59. doi:10.1186/1755-8794-3-59. PMID 21162720. 
  46. ^ Hasumi H, Baba M, Hasumi Y, Huang Y, Oh H, Hughes RM, et al. (November 2012). "Regulation of mitochondrial oxidative metabolism by tumor suppressor FLCN". Journal of the National Cancer Institute. 104 (22): 1750–64. doi:10.1093/jnci/djs418. PMID 23150719. 
  47. ^ Hasumi Y, Baba M, Hasumi H, Huang Y, Lang M, Reindorf R, et al. (November 2014). "Folliculin (Flcn) inactivation leads to murine cardiac hypertrophy through mTORC1 deregulation". Human Molecular Genetics. 23 (21): 5706–19. doi:10.1093/hmg/ddu286. PMID 24908670. 
  48. ^ Medvetz DA, Khabibullin D, Hariharan V, Ongusaha PP, Goncharova EA, Schlechter T, Darling TN, Hofmann I, Krymskaya VP, Liao JK, Huang H, Henske EP (2012). "Folliculin, the product of the Birt-Hogg-Dube tumor suppressor gene, interacts with the adherens junction protein p0071 to regulate cell-cell adhesion". PloS One. 7 (11): e47842. doi:10.1371/journal.pone.0047842. PMID 23139756. 
  49. ^ Nahorski MS, Seabra L, Straatman-Iwanowska A, Wingenfeld A, Reiman A, Lu X, et al. (December 2012). "Folliculin interacts with p0071 (plakophilin-4) and deficiency is associated with disordered RhoA signalling, epithelial polarization and cytokinesis". Human Molecular Genetics. 21 (24): 5268–79. doi:10.1093/hmg/dds378. PMID 22965878. 
  50. ^ Goncharova EA, Goncharov DA, James ML, Atochina-Vasserman EN, Stepanova V, Hong SB, et al. (April 2014). "Folliculin controls lung alveolar enlargement and epithelial cell survival through E-cadherin, LKB1, and AMPK". Cell Reports. 7 (2): 412–23. doi:10.1016/j.celrep.2014.03.025. PMID 24726356. 
  51. ^ Khabibullin D, Medvetz DA, Pinilla M, Hariharan V, Li C, Hergrueter A, et al. (August 2014). "Folliculin regulates cell-cell adhesion, AMPK, and mTORC1 in a cell-type-specific manner in lung-derived cells". Physiological Reports. 2 (8). doi:10.14814/phy2.12107. PMID 25121506. 
  52. ^ Kennedy JC, Khabibullin D, Henske EP (April 2016). "Mechanisms of pulmonary cyst pathogenesis in Birt-Hogg-Dube syndrome: The stretch hypothesis". Seminars in Cell & Developmental Biology. 52: 47–52. doi:10.1016/j.semcdb.2016.02.014. PMID 26877139. 
  53. ^ Esteban MA, Harten SK, Tran MG, Maxwell PH (July 2006). "Formation of primary cilia in the renal epithelium is regulated by the von Hippel-Lindau tumor suppressor protein". Journal of the American Society of Nephrology. 17 (7): 1801–6. doi:10.1681/ASN.2006020181. PMID 16775032. 
  54. ^ Hartman TR, Liu D, Zilfou JT, Robb V, Morrison T, Watnick T, Henske EP (January 2009). "The tuberous sclerosis proteins regulate formation of the primary cilium via a rapamycin-insensitive and polycystin 1-independent pathway". Human Molecular Genetics. 18 (1): 151–63. doi:10.1093/hmg/ddn325. PMID 18845692. 
  55. ^ a b Luijten MN, Basten SG, Claessens T, Vernooij M, Scott CL, Janssen R, Easton JA, Kamps MA, Vreeburg M, Broers JL, van Geel M, Menko FH, Harbottle RP, Nookala RK, Tee AR, Land SC, Giles RH, Coull BJ, van Steensel MA (November 2013). "Birt-Hogg-Dube syndrome is a novel ciliopathy". Human Molecular Genetics. 22 (21): 4383–97. doi:10.1093/hmg/ddt288. PMID 23784378. 
  56. ^ a b c Zhong M, Zhao X, Li J, Yuan W, Yan G, Tong M, Guo S, Zhu Y, Jiang Y, Liu Y, Jiang Y (May 2016). "Tumor Suppressor Folliculin Regulates mTORC1 through Primary Cilia". The Journal of Biological Chemistry. 291 (22): 11689–97. doi:10.1074/jbc.M116.719997. PMID 27072130. 
  57. ^ Boehlke C, Kotsis F, Patel V, Braeg S, Voelker H, Bredt S, et al. (November 2010). "Primary cilia regulate mTORC1 activity and cell size through Lkb1". Nature Cell Biology. 12 (11): 1115–22. doi:10.1038/ncb2117. PMID 20972424. 
  58. ^ a b Possik E, Jalali Z, Nouët Y, Yan M, Gingras MC, Schmeisser K, Panaite L, Dupuy F, Kharitidi D, Chotard L, Jones RG, Hall DH, Pause A (April 2014). "Folliculin regulates ampk-dependent autophagy and metabolic stress survival". PLoS Genetics. 10 (4): e1004273. doi:10.1371/journal.pgen.1004273. PMID 24763318. 
  59. ^ Dunlop EA, Seifan S, Claessens T, Behrends C, Kamps MA, Rozycka E, et al. (October 2014). "FLCN, a novel autophagy component, interacts with GABARAP and is regulated by ULK1 phosphorylation". Autophagy. 10 (10): 1749–60. doi:10.4161/auto.29640. PMID 25126726. 
  60. ^ Bastola P, Stratton Y, Kellner E, Mikhaylova O, Yi Y, Sartor MA, Medvedovic M, Biesiada J, Meller J, Czyzyk-Krzeska MF (2013). "Folliculin contributes to VHL tumor suppressing activity in renal cancer through regulation of autophagy". PloS One. 8 (7): e70030. doi:10.1371/journal.pone.0070030. PMID 23922894. 
  61. ^ Cash TP, Gruber JJ, Hartman TR, Henske EP, Simon MC (June 2011). "Loss of the Birt-Hogg-Dubé tumor suppressor results in apoptotic resistance due to aberrant TGFβ-mediated transcription". Oncogene. 30 (22): 2534–46. doi:10.1038/onc.2010.628. PMID 21258407. 
  62. ^ a b Yan M, Gingras MC, Dunlop EA, Nouët Y, Dupuy F, Jalali Z, et al. (June 2014). "The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation". The Journal of Clinical Investigation. 124 (6): 2640–50. doi:10.1172/JCI71749. PMID 24762438. 
  63. ^ Yan M, Audet-Walsh É, Manteghi S, Dufour CR, Walker B, Baba M, St-Pierre J, Giguère V, Pause A (May 2016). "Chronic AMPK activation via loss of FLCN induces functional beige adipose tissue through PGC-1α/ERRα". Genes & Development. 30 (9): 1034–46. doi:10.1101/gad.281410.116. PMID 27151976. 
  64. ^ Preston RS, Philp A, Claessens T, Gijezen L, Dydensborg AB, Dunlop EA, et al. (March 2011). "Absence of the Birt-Hogg-Dubé gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility". Oncogene. 30 (10): 1159–73. doi:10.1038/onc.2010.497. PMID 21057536. 

Further reading

  • Schmidt LS, Linehan WM (October 2015). "Molecular genetics and clinical features of Birt-Hogg-Dubé syndrome". Nature Reviews. Urology. 12 (10): 558–69. doi:10.1038/nrurol.2015.206. PMID 26334087. 
  • Tee AR, Pause A (September 2013). "Birt-Hogg-Dubé: tumour suppressor function and signalling dynamics central to folliculin". Familial Cancer. 12 (3): 367–72. doi:10.1007/s10689-012-9576-9. PMID 23096221. 

External links

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.

Folliculin C-terminal domain Provide feedback

This is the C-terminal domain of folliculin. It has guanine nucleotide exchange factor (GEF) activity [1].

Literature references

  1. Nookala RK, Langemeyer L, Pacitto A, Ochoa-Montano B, Donaldson JC, Blaszczyk BK, Chirgadze DY, Barr FA, Bazan JF, Blundell TL;, Open Biol. 2012;2:120071.: Crystal structure of folliculin reveals a hidDENN function in genetically inherited renal cancer. PUBMED:22977732 EPMC:22977732


This tab holds annotation information from the InterPro database.

InterPro entry IPR032035

This is the C-terminal domain of folliculin. This domain shares structural similarity with DENN domain of DENN1B (a Rab GEF), and has guanine nucleotide exchange factor (GEF) activity [PUBMED:22977732].

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

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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 (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...

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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
(15)
Full
(230)
Representative proteomes UniProt
(315)
NCBI
(550)
Meta
(0)
RP15
(79)
RP35
(123)
RP55
(184)
RP75
(218)
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

Format an alignment

  Seed
(15)
Full
(230)
Representative proteomes UniProt
(315)
NCBI
(550)
Meta
(0)
RP15
(79)
RP35
(123)
RP55
(184)
RP75
(218)
Alignment:
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Sequence:
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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
(15)
Full
(230)
Representative proteomes UniProt
(315)
NCBI
(550)
Meta
(0)
RP15
(79)
RP35
(123)
RP55
(184)
RP75
(218)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download    
Gzipped Download   Download   Download   Download   Download   Download   Download   Download    

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

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 View help on the curation process

Seed source: PDB:3v42
Previous IDs: none
Type: Domain
Author: Eberhardt R
Number in seed: 15
Number in full: 230
Average length of the domain: 201.70 aa
Average identity of full alignment: 30 %
Average coverage of the sequence by the domain: 38.46 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 26740544 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 27.0 27.0
Trusted cut-off 27.6 27.3
Noise cut-off 26.7 26.7
Model length: 228
Family (HMM) version: 4
Download: download the raw HMM for this family

Species distribution

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Archea Archea Eukaryota Eukaryota
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Viroids Viroids Unclassified sequence Unclassified sequence

Selections

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This 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...

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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 Folliculin_C domain has been found. There are 2 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.

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