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 (see <PDOC50826>), PLAT (see <PDOC50095>), PH (see <PDOC50003>), PPR, WD-40 (see <PDOC00574>), GRAM or C1 (see <PDOC00379>). The function of DENN domain remains to date unclear, although it appears to represent a good candidate for a GTP/GDP exchange activity [1,2,3,4,5].

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 (see <PDB:3TW8>), 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 α/β three layered sandwich domain with a central sheet of 5-strands. The dDENN domain is an all-α helical domain, whose core contains two α-hairpins which diverge rapidly in sequence [3,5].

Divergent types of the tripartite DENN domain have also been detected in other protein families [4]:

• Folliculin (FLCN), a tumor suppressor protein disrupted in various cancers and the Birt-Hogg-Dubé syndrome, and Smith-Magenis syndrome chromosomal region candidate eight protein (SMCR8), which has been implicated in autophagy [5].
• 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).

We developed both a profile that covers the entire tripartite DENN domains and profiles covering the entire more divergent types of DENN domains.