Peroxisomal targeting of hepatic glycolate oxidase

Recalcati, Stefania; Menotti, Eric; Conte, Diana; Kühn, Lothar

doi:10.1016/s0168-8278(00)80631-5

Cited by 1 publication

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“…We are currently investigating the nature of the N4BP3-containing vesicles. The presence of a consensus microsome-targeting signal (40) in the carboxyl terminus of both mouse and human N4BP3 suggests that these vesicles might be related to peroxisomes or other single-membrane organelles. Alternatively, these vesicles might be part of the endocytic system that regulates turnover of activated membrane receptors.…”

Section: Nedd4 Developmental Targetsmentioning

confidence: 99%

Identification of Developmentally Expressed Proteins That Functionally Interact with Nedd4 Ubiquitin Ligase

Murillas¹,

Simms²,

Hatakeyama³

et al. 2002

Journal of Biological Chemistry

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Nedd4 is a HECT domain-containing ubiquitin ligase that mediates ubiquitylation and proteasome degradation of target proteins. The molecular basis for the interaction of Nedd4 with substrates lies in its WW domains, which can bind proline-rich (PY) domains in target proteins. Nedd4 is a developmentally expressed protein and may have a fundamental role to play in embryonic processes. However, whether Nedd4 has such a function is currently unknown, in part because few developmentally regulated ubiquitylation substrates have been identified or characterized. We have carried out a yeast two-hybrid screen and identified four proteins expressed in the mid-gestation embryo that are able to interact with Nedd4. Characterization of their functional interaction with Nedd4 in vitro and in vivo demonstrated that three of the four are bona fide Nedd4 binding partners, and two have the capacity to be ubiquitylation substrates. One of these is the first identified nonviral substrate for Nedd4-mediated monoubiquitylation. Interestingly, neither of these two ubiquitylated proteins interacts with Nedd4 through PYmediated mechanisms. For one of the three Nedd4 binding partners, there was no discernable evidence of ubiquitylation. However, this protein clearly associates with Nedd4 through its PY domains and can alter the location of Nedd4 in cells, suggesting a role other than as a ubiquitylation substrate.A large number of recent findings have highlighted the importance of protein modification by the covalent addition of small polypeptides (1, 2). The prototype for this is ubiquitin, a 76-amino acid polypeptide that, when added in multiple units to form a chain (polyubiquitylation), targets proteins for degradation by the 26 S proteasome (3). In contrast, the addition of a single ubiquitin moiety (monoubiquitylation) has been implicated in receptor endocytosis (4, 5), activation of gene expression through histone modification (6), and targeting of proteins to specific subnuclear locations (7). In addition, protein modification by the ubiquitin-like proteins SUMO and Nedd8 has been found to have a wide range of functions, from control of subcellular localization to modulation of protein stability (8, 9).Ubiquitylation occurs at lysine residues, either within target proteins or on ubiquitin already attached to the target protein, and involves three distinct enzymatic activities. Ubiquitin-activating enzyme (E1) 1 activates ubiquitin to a high energy state in an ATP-dependent manner and then transfers it to a ubiquitin-conjugating enzyme (E2). The E2 either can transfer ubiquitin directly to the target substrate or interact with a ubiquitin protein ligase (E3), which then mediates the transfer of ubiquitin to substrate proteins (10). There are two major classes of E3 ubiquitin ligases. Those containing a RING finger motif act in concert with E2 enzymes in the direct transfer of ubiquitin from the E2 to the target protein (11). Members of the second class of E3 ubiquitin ligases accept activated ubiquitin from the E2 and transfer it ...

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Section: Nedd4 Developmental Targetsmentioning

confidence: 99%