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EDEMs:Edit

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· in mammalian cells there are EDEM1, EDEM2 and EDEM3 (Olivari et al., 2007; FEBS Letters)

o human EDEM1 (KIAA0212) is closely related to the previously characterized mouse EDEM

o human EDEM2 (C20orf31) (Mast et al., 2005; Glycobiol)

o human EDEM3 (C1orf22)

· upregulated upon ER stress è mechanism to enable quick cell recovery upon UPR

· intralumenal level of EDEM1,2 and 3 is adapted to variations in ER cargo load or in response to accumulation of misfolded polypeptides in the ER lumen (Olivari & Molinari, 2007; FEBS Letters)

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Mouse EDEM1 (Hirao, 2006)

· glycosyl hydrolase family 47, α1,2-mannosidase (?) à not sure yet if de-mannosylation of ERAD substrates is mediated by one or by more members of the GH47 family (ERManI, EDEMs, Golgi mannosidases)

· aa sequences are different from other lectins

· lack two conserved cysteine residues thought to be conserved in active mannosidases (Lipari et al., 1996; JBC), but they are most probably NOT inactive lectins because these two cysteines were shown to be dispensable for glycanase activity (Tatara et al., 2005; Biosci Biotechnol Biochem), but so far no in vitro activity has been confirmed; e.g. Trichoderma reseei α1,2-mannosidase also lacks these conserved cysteine residues and is still an active mannosidase, indicating that the disulfide is not essential for hydrolase activity (Van Petegem et al., 2001; J Mol Biol)

· have 3D structure of catalytic site of ERManI and also conserved residues required to bind kifunensine (Karaveg et al., 2005; JBC)

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· extract misfolded glycoproteins, but not glycoproteins undergoing productive folding, from the calnexin cycle è upregulation of EDEM during ER stress may promote cell recovery by clearing the calnexin cycle; EDEM overexpression: faster release of folding-incompetent proteins; EDEM downregulation: prolongs folding attemps & delays ERAD (Molinari et al., 2003; Science)

· sequence relationship shared by the EDEM homologs exists only in the mannosidase homology domain (MHD); they each have variable N- and C-terminal extensions that do not share sequence similarity with the other two homologs (Mast et al., 2005; Glycobiol)

· C-terminal domains: EDEM1 extension contains a putative ATP/GTP-binding site motif A (P-loop), EDEM2 has no recognizable motifs, EDEM3 has a putative protease-associated domain in the middle of the extended tail è the differences in sequence between the EDEM homologs suggest overlapping but specific roles for each member (Mast et al., 2005; Glycobiol)

· based on Unigene expression profile, EDEM1,2 and 3 are frequently expressed in the same organs but with some difference, e.g. EDEM1 is present alone in the mouse parathyroid and EDEM2 in the adrenal gland (Olivari & Molinari, 2007; FEBS Letters)

· alignment of EDEMs and other GH47 family members shows ~440 aa conserved region = manosidase homology domain (Olivari & Molinari, 2007; FEBS Letters)

· not clear if role of the EDEM proteins is redundant in the cell

·

Figure 4. Schematic representation of GH47 family members in mammals (Olivari & Molinari, 2007). The conserved mannosidase homology domain is violet. There is little or no conservation among family members beyond this domain. EDEM3 contains a protease-associated domain (PA) and the KDEL retention signal. The TM regions of ERManI and of Golgi ManIA,B and C are shown in dark blue, the putative TM domain of EDEM1 is shown in light blue.

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