Birt-Hogg-Dube' syndrome, a disorder characterised by benign tumours of the hair follicle, lung cysts and renal neoplasia, is caused by germline mutations in the BHD(FLCN) gene; this encodes a tumour suppressor protein, folliculin (FLCN), of unknown function []. The folliculin- interacting protein, FNIP1, has also been identified and shown to interact with 5' AMP-activated protein kinase (AMPK), which plays a vital role in energy sensing []. Together, then, it is thought that folliculin (mutated in Birt-Hogg-Dube' syndrome) and its interaction partner, FNIP1, may be involved in energy and/or nutrient sensing via the AMPK and mTOR signalling pathways.FNIP1 has a homologue, FNIP2, which also interacts with FLCN and AMPK. C-terminally-deleted FLCN mutants, like those produced by germline mutations in BHD patients, do not bind FNIP2, suggesting that FLCN tumour-suppressor function may be facilitated by interactions with both FNIP1 and FNIP2 via its C terminus []. FNIP1 and FNIP2 are able to form homo- or heteromeric multimers, and may hence function either independently or cooperatively with FLCN [].This entry represents the FNIP family, including FNIP1 and FNIP2.
The tripartite DENN (after differentially expressed in neoplastic versus normal cells) domain is found in several proteins that share common structural features and have been shown to be guanine nucleotide exchange factors (GEFs) for Rab GTPases, which are regulators of practically all membrane trafficking events in eukaryotes. The tripartite DENN domain is composed of three distinct modules which are always associated due to functional and/or structural constraints: upstream DENN or uDENN, the better conserved central or core or cDENN, and downstream or dDENN regions. The tripartite DENN domain is found associated with other domains, such as RUN, PLAT, PH, PPR, WD-40, GRAM or C1. The function of DENN domain remains to date unclear, although it appears to represent a good candidate for a GTP/GDP exchangeactivity [, , , , ].Some proteins known to contain a tripartite DENN domain are listed below:Rat Rab3 GDP/GTP exchange protein (Rab3GEP).Human mitogen-activated protein kinase activating protein containing death domain (MADD). It is orthologous to Rab3GEP.Caenorhabditis elegans regulator of presynaptic activity aex-3, the ortholog of Rab3GEP.Mouse Rab6 interacting protein 1 (Rab6IP1).Human SET domain-binding factor 1(SBF1).Human suppressor of tumoreginicity 5 (ST5).Human C-MYC promoter-binding protein IRLB.The DENN domain forms a heart-shaped structure, with the N-terminal residues forming one and the C-terminal residues forming the second one. The N-terminal half forms the uDENN domain and consists of a central antiparallel β-sheet layered between one helix and two helices. A long random-coil region links the two lobes. The C-terminal lobe is composed of the cDENN and dDENN domains. The cDENN domain is an alpha/beta three layered sandwich domain with a central sheet of 5-strands. The dDENN domain is an all-alpha helical domain, whose core contains two alpha-hairpins which divergerapidly in sequence [, ].Divergent types of the tripartite DENN domain have also been detected in other protein families []:Folliculin (FLCN), a tumor suppressor protein disrupted in various cancers and the Birt-Hogg-Dube syndrome, and Smith-Magenis syndrome chromosomal region candidate eight protein (SMCR8), which has been implicated in autophagy [].FLCN-interacting proteins (FNIP1 and FNIP2), interact with FLCN and function in conjunction with it to regulate cellular energy metabolism both in the kidney tissue and B-cells.C9ORF72 protein, expansions of the hexanucleotide GGGGCC in the first intron of its gene have been implicated in amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD).This entry represents the FNIP1/FNIP2-type divergent tripartite DENN domain.
