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First published online September 9, 2005
doi: 10.1242/10.1242/jcs.02595

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C-terminal EH-domain-containing proteins: consensus for a role in endocytic trafficking, EH?

Department of Biochemistry and Molecular Biology and Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA

View larger version (12K): [in a new window]   Fig. 1. Comparison of C-terminal EHD protein architecture with other EHD proteins. Mammalian C-terminal EHD proteins comprise 534-541 amino acids and have three recognizable domains: an N-terminal nucleotide-binding region (light blue), a C-terminal EH domain (green), and a central coiled-coil region (gray). The motif homologous to the P-loop (or H-Ras G1 motif) is indicated, beginning with glycine at residue 65 (shown in red). Also denoted is the conserved tryptophan (W485) essential for EH-domain-mediated binding. For comparison, the EHD proteins Eps15 and intersectin1 are shown. These contain the following domains: DPW (orange); aspartate-proline-tryptophan; ubiquitin interacting motif, UIM (purple); src homology domain 3, SH3 (dark blue).

View larger version (106K): [in a new window]   Fig. 2. Alignment of human and mouse C-terminal EHD proteins. Full-length amino acid sequences of human and mouse C-terminal EHD proteins were aligned by the ClustalW Multiple Sequences Alignment in the Vector NTI software program (Invitrogen, Carlsbad, CA). Shaded red letters indicate an identical match between all eight sequences, unshaded blue letters denote identity with the consensus sequence, while shaded black letters indicate similarity (but not identity) with the same consensus sequence. Unshaded green letters denote amino acids with little similarity to the consensus sequence. Unshaded black letters are used when there is no consensus residue.

View larger version (23K): [in a new window]   Fig. 3. Involvement of mammalian C-terminal EHD proteins in endocytic pathways. Mammalian EHD proteins affect a wide range of endocytic events. EHD1 plays a central role in regulating the recycling of various receptors from the perinuclear recycling compartment to the plasma membrane. These include receptors that have been internalized either through clathrin-coated pits (e.g. the transferrin receptor, TfR) or independently of clathrin [e.g. major histocompatability complex class I molecules (MHC-I) and integrins]. The latter are regulated by the small GTPase Arf6. An endocytic regulatory role similar to that of EHD1 has been proposed for EHD4, and both EHD proteins are involved in the Arf6 recycling pathway. However, EHD1 has also been implicated at earlier stages of the endocytic pathway, including the internalization of insulin-like growth factor 1 receptor (IGF-1R). Both EHD2 and EHD4 have also been linked to early endocytic events, regulating internalization of transferrin and nerve growth factor receptors (NGF-R, TrkA), respectively. The function of EHD3 has not yet been elucidated. The relationship between key Rab-family members and EHD proteins remains an open question. EE/SE, early endosome/sorting endosome; ERC, endocytic recycling compartment; GLUT4, glucose transporter isoform 4.

View larger version (91K): [in a new window]   Fig. 4. Colocalization of internalized transferrin vesicles with EHD1. Human HeLa cells were transfected with GFP-EHD1 and subjected to a 10-minute pulse with labeled transferrin (transferrin 568 nm). As depicted in A, transferrin is observed in a range of peripheral and perinuclear vesicles, whereas EHD1 localizes to tubulo-vesicular membranes. The merged image shows a partial colocalization of internalized transferrin with vesicular EHD1-containing structures. The yellow box in A marks the inset depicted as B. Examples of transferrin-containing vesicular structures aligned with EHD1-containing tubular membranes are marked by white arrows. Bar, 10 µm.

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