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.

Highlights

  • Protein domains are modular cassettes with conserved folds that are often found in otherwise unrelated proteins

  • It is clear that DENN domain proteins regulate Rab GTPases and represent a new class of membrane trafficking proteins

  • We need to clarify that, for the many DENN domain proteins shown to have GEF activity, the activity is mediated by the DENN domain

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Summary

Identification of the DENN Domain

Chow and Lee [9] originally cloned an open reading frame that they named DENN based on its variable mRNA expression levels in tissues and cell lines. The protein was named MADD (MAPK-activating protein containing a death domain) [10] Databases such as Pfam and PROSITE were established in part to identify and annotate protein modules. These initiatives recognized that a portion of the N-terminal region of DENN/ MADD was similar to regions in several otherwise unrelated proteins, resulting in the concept of a DENN domain. One such protein was Rab6IP1 (Rab6-interacting protein 1), identified in a two-hybrid screen with Rab6 [11]. Like DENN domains, AH domains may function in the regulation of GTPases

DENN Domain Protein Families in Humans
DENN Domains and DENN Domain Proteins as Integrators of Rab Pathways
Structure of the DENN Domain
Conclusion and Perspectives
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