We previously solved the crystal structure of EHD2, revealing that EHDs are dynamin-related proteins involved in nucleotide-dependent membrane remodeling ( Daumke et al., 2007 ). EHDs contain an amino (N)-terminal GTPase (G) domain, followed by a helical domain, a linker region, and a C-terminal EHD known to bind to linear Asn-Pro-Phe peptide (NPF) motifs ( Figure 1A). The mammalian genome encodes four EHDs, EHD1–4, while Caenorhabditis elegans and Drosophila each has a single EHD gene, rme-1 and Past-1, respectively. Proteins within the Eps15 homology domain–containing protein family (EHDs) have been shown to participate in the remodeling of membranes in the endosomal system (reviewed in Naslavsky and Caplan, 2011 ). Internalization and recycling of cell surface receptors involves multiple membrane sculpting and budding events in the cell.

Thus, following the identification of caveolin and cavins, EHD2 constitutes a third structural component of caveolae involved in controlling the stability and turnover of this organelle. Assembly of EHD2 stabilized and constrained caveolae to the plasma membrane to control turnover, and depletion of EHD2, resulting in endocytic and more dynamic and short-lived caveolae. EHD2 was not essential for the formation or shaping of caveolae, but high levels of EHD2 caused distortion and loss of endogenous caveolae. While the EHD of EHD2 is dispensable for targeting, we identified a loop in the nucleotide-binding domain that, together with ATP binding, is required for caveolar localization.

EHD2 interacts with pacsin2 and cavin1, and ordered membrane assembly of EHD2 is dependent on cavin1 and caveolar integrity. In this paper, we report that EHD2 is specifically and stably associated with caveolae at the plasma membrane and not involved in clathrin-mediated endocytosis or endosomal recycling, as previously suggested. EHD2 dimers oligomerize into rings on highly curved membranes, resulting in stimulation of the intrinsic ATPase activity.

Eps15 homology domain–containing 2 (EHD2) belongs to the EHD-containing protein family of dynamin-related ATPases involved in membrane remodeling in the endosomal system.

Robert phelps icq number