The tripartite DENN (Differentially Expressed in Normal and Neoplastic Cells) domain is an evolutionarily conserved protein module found in several proteins involved in Rab-mediated processes and, in some cases, regulation of MAPK (Mitogen-Activated Protein Kinase) signalling pathways and related proteins in eukaryotic organisms. The DENN domain consists of three subdomains: uDENN (upstream DENN) … expand

The tripartite DENN (Differentially Expressed in Normal and Neoplastic Cells) domain is an evolutionarily conserved protein module found in several proteins involved in Rab-mediated processes and, in some cases, regulation of MAPK (Mitogen-Activated Protein Kinase) signalling pathways and related proteins in eukaryotic organisms. The DENN domain consists of three subdomains: uDENN (upstream DENN) IPR005113 the core DENN domain IPR001194 and dDENN (downstream DENN) IPR005112 which are structurally distinct but functionally interconnected due to their roles in Rab GTPase activation. Recent studies have confirmed the DENN domain's function as a guanine nucleotide exchange factor (GEF) for Rab GTPases, facilitating the exchange of GDP for GTP to activate Rabs. This activity has been demonstrated for various DENN proteins, such as DENND1A and DENND1B, which specifically activate Rab35, and DENND2B, which serves as a GEF for Rab10 and Rab13, influencing processes like primary ciliogenesis and epithelial cancer development [ PUBMED:38296963 PUBMED:35196081 PUBMED:37454296 ].

The tripartite structure of the DENN domain, comprising uDENN, DENN itself, and dDENN, features distinct patterns of sequence conservation and variable interdomain lengths that suggest functional specialisation. Structural studies have revealed conserved residues critical for Rab binding and catalytic activity, emphasising the role of DENN domains in spatially and temporally regulating membrane trafficking events [ PUBMED:22065758 ]. Additionally, DENN domains are often associated with other domains such as RUN IPR004012 PLAT IPR001024 which may further enhance their functional versatility in cellular signalling pathways [ PUBMED:12906859 ].

Some proteins known to contain a tripartite DENN domain include:

• Human mitogen-activated protein kinase activating protein containing death domain (MADD) Q8WXG6 orthologous to Rab3GEP
• Human SET domain-binding factor 1 (SBF1) Q86WG5
• Human DENN domain-containing protein 2B P78524
• Human C-myc promoter-binding protein Q7Z401

In Arabidopsis, SCD1 is a unique gene encoding for the only protein containing a complete DENN domain. SCD1 is part of a protein complex that interacts with the exocyst complex and the RabE1 family of GTPases. It is also involved in activating innate immune responses against bacteria [ PUBMED:20472560 PUBMED:28970336 ].

Recent findings highlight the broader target spectrum of DENN domains than previously appreciated. For example, DENND2B interacts with Rab35 as both an effector and a GEF at intercellular bridges during cytokinesis. These discoveries underscore the importance of DENN domain proteins in regulating diverse cellular processes such as vesicle trafficking, signal transduction, ciliogenesis, and cancer progression [ PUBMED:38296963 ].

This entry represents the uDENN domain.