DENN domain proteins: regulators of Rab GTPases

Abstract

The DENN domain is a common, evolutionarily ancient, and conserved protein module, yet it has gone largely unstudied; until recently, little was known regarding its functional roles. New studies reveal that various DENN domains interact directly with members of the Rab family of small GTPases and that DENN domains function enzymatically as Rab-specific guanine nucleotide exchange factors. Thus, DENN domain proteins appear to be generalized regulators of Rab function. Study of these proteins will provide new insights into Rab-mediated membrane trafficking pathways.

FIGURE 1.

Domain models of the 18 DENN domain-bearing proteins encoded in the human genome. The gene name is listed on the left, with the protein name in parentheses when appropriate. u, uDENN module; d, dDENN module; CB, clathrin-binding motif; PRD, proline-rich domain; AP-2IM, AP-2 interaction motif; MABP, MVB12-associated β-prism; PPR, pentatricopeptide repeat; CalB, calmodulin-binding domain; NLS, nuclear localization sequence; poly-E, polyglutamic acid domain; ISRE, interferon-stimulated response element; poly-Q, polyglutamine domain; SRD, serine-rich domain; poly-D, polyaspartic acid domain; PLAT, polycystin-1/lipoxygenase/α-toxin domain; GRAM, glucosyltransferase/Rab-like GTPase activator/myotubularin domain; pseudo-phosph, pseudo-phosphatase domain; DD, death domain.

FIGURE 2.

Amino acid sequence alignment of the 18 human DENN domain proteins. The amino acid sequences of the DENN domains correspond to the sequences of the UniProt long isoforms listed in Table 1. Alignment was performed with ClustalW and manually modified using Jalview. Shaded boxes represent conserved residues, with darker shadings based on increasing percent identity. The dashed border for the N terminus of the DENN module is used to highlight the varying lengths of the linker regions between the uDENN and DENN modules, where some DENN modules begin at the start of the dashed line and others begin at the start of the solid line. Secondary structure predictions are also indicated along the gray dashed line below the alignment. β-Strands and α-helices are represented as black arrows and red rectangles, respectively.

FIGURE 2.

Amino acid sequence alignment of the 18 human DENN domain proteins. The amino acid sequences of the DENN domains correspond to the sequences of the UniProt long isoforms listed in Table 1. Alignment was performed with ClustalW and manually modified using Jalview. Shaded boxes represent conserved residues, with darker shadings based on increasing percent identity. The dashed border for the N terminus of the DENN module is used to highlight the varying lengths of the linker regions between the uDENN and DENN modules, where some DENN modules begin at the start of the dashed line and others begin at the start of the solid line. Secondary structure predictions are also indicated along the gray dashed line below the alignment. β-Strands and α-helices are represented as black arrows and red rectangles, respectively.

FIGURE 3.

Coordination between endosome-derived carriers (Rab11) and Golgi acceptor compartments (Rab6 and Rab39) via Rab6IP1. Rab6IP1 binds GTP-bound Rab11, likely through its uDENN module (u), and binds Rab6 through its first RUN domain while functioning as a GEF toward Rab39. Rab6IP1 is targeted to the Golgi by Rab6 and to recycling endosomes by Rab11, providing a molecular link between Rab6, Rab11, and Rab39. d, dDENN domain; poly-D, polyaspartic acid domain; PLAT, polycystin-1/lipoxygenase/α-toxin domain.