Ubiquitination of the PEST-like Endocytosis Signal of the Yeast a-Factor Receptor

Roth, Allan C.; Davis, Nicholas G.

doi:10.1074/jbc.275.11.8143

Cited by 104 publications

(115 citation statements)

References 40 publications

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“…Lys-48-linked ubiquitin tagging is mostly used to target proteins for degradation by the proteasome, whereas Lys-63-linked ubiquitination has been linked to numerous cellular events that do not rely on the degradative signaling via the proteasome. Of these, the endocytosis of membrane proteins (41)(42)(43)(44), protein sorting and trafficking (45)(46)(47), and post-replicative DNA repair (48) are well characterized. Doss-Pepe et al (49) have reported recently that Parkin has dual specificity for the assembly of ubiquitin chains through two different linkages to the substrate (Ub-Lys-48 and Ub-Lys-63).…”

Section: Discussionmentioning

confidence: 99%

Parkin Ubiquitinates and Promotes the Degradation of RanBP2

Min

Rhim

et al. 2006

Journal of Biological Chemistry

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Parkinson disease (PD) is a common neurodegenerative disorder, which involves the deterioration of dopaminergic neurons in the pars compacta of the substantia nigra. The etiology of PD is still unknown, but recent identification of mutations in familial cases of PD has advanced the understanding of the molecular mechanisms of this neurological disease. Mutations in the parkin gene, which encodes for ubiquitin-protein ligase (E3), have been implicated in autosomal recessive juvenile Parkinsonism, an early onset and common familial form of PD. Here we reported that Parkin selectively binds to RanBP2, which is localized in the cytoplasmic filament of the nuclear pore complex and belongs to the small ubiquitin-related modifier E3 ligase family. We also demonstrated that RanBP2 becomes a target for Parkin E3 ubiquitin-ligase and is processed via Parkin-mediated ubiquitination and subsequent proteasomal degradation. Furthermore, Parkin controls the intracellular levels of sumoylated HDAC4, as a result of the ubiquitination and degradation of RanBP2. Our findings suggested that the intracellular levels of RanBP2 and its functional activity may be modulated by Parkinmediated ubiquitination and proteasomal pathways. Parkinson disease (PD)2 is a major neurodegenerative disease characterized by a distinct set of movement disorders, including muscle rigidity, tremor, and bradykinesia (1). In PD, the level of dopamine is decreased in the striatum, most severely in the putamen. This is largely a result of the deterioration of dopaminergic neurons in the substantia nigra pars compacta (2-4). The etiology of PD remains poorly understood, but several genetic loci have been implicated in the pathogenesis of familial forms of PD. First, two missense mutations of ␣-synuclein have been linked to a rare dominant form of PD (5). Second, parkin has been identified as the causative gene of early onset autosomal recessive juvenile parkinsonism (AR-JP) (6), and a missense mutation in the ubiquitin (Ub) C-terminal hydrolase L1 appears to be responsible for a dominant form of PD (7). Most recently, mutations in DJ-1 and PTENinduced putative kinase-1 have been correlated with the incidences of familial PD (8, 9).The structure of Parkin contains a C-terminal RING-IBR-RING motif and an N-terminal region with homology to ubiquitin (10 -12). Proteins destined to degrade in the proteasomes are subject to covalent modification by ubiquitin as a small protein tag. Ubiquitination proceeds through a sequential enzymatic reaction composed of ubiquitinactivating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin-protein ligase (E3) (13). Based on the previous findings that numerous proteins with RING finger motifs have E3 ubiquitin-ligase activity, several studies have revealed that Parkin has an ubiquitin E3 ligase activity. The exquisite specificity for the proteins to be ubiquitinated is usually determined by a diverse family of E3s with a specific E2.Based on the functional role of Parkin, it can be surmised that the loss of Parkin resul...

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Section: Discussionmentioning

confidence: 99%

Parkin Ubiquitinates and Promotes the Degradation of RanBP2

Min

Rhim

et al. 2006

Journal of Biological Chemistry

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“…The acronym PEST refers to an enrichment of proline (P), aspartate and glutamate (E), serine (S), and threonine (T) residues (Rogers et al 1986). In many cases, PEST sequences are targets for phosphorylation and implicated in the regulation of protein turnover (Rechsteiner and Rogers 1996;Marchal et al 1998;Roth and Davis 2000). Both PEST-1 (amino acid residues 544-560) and PEST-2 (residues 843-893) of FRQ appear to be phosphorylated in vivo Schafmeier et al 2006).…”

Section: Physical Properties Of Frqmentioning

confidence: 99%

Transcriptional and post-transcriptional regulation of the circadian clock of cyanobacteria and Neurospora

Brunner¹,

Schafmeier²

2006

Genes Dev.

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Circadian clocks are self-sustained oscillators modulating rhythmic transcription of large numbers of genes. Clock-controlled gene expression manifests in circadian rhythmicity of many physiological and behavioral functions. In eukaryotes, expression of core clock components is organized in a network of interconnected positive and negative feedback loops. This network is thought to constitute the pacemaker that generates circadian rhythmicity. The network of interconnected loops is embedded in a supra-net via a large number of interacting factors that affect expression and function of core clock components on transcriptional and post-transcriptional levels. In particular, phosphorylation and dephosphorylation of clock components are critical processes ensuring robust self-sustained circadian rhythmicity and entrainment of clocks to external cues. In cyanobacteria, three clock proteins have the capacity to generate a self-sustained circadian rhythm of autophosphorylation and dephosphorylation independent of transcription and translation. This phosphorylation rhythm regulates the function of these clock components, which then facilitate rhythmic gene transcription, including negative feedback on their own genes. In this article, we briefly present the mechanism of clock function in cyanobacteria. We then discuss in detail the contribution of transcriptional feedback and protein phosphorylation to various functional aspects of the circadian clock of Neurospora crassa.Circadian rhythms are found in numerous light-perceiving organisms including cyanobacteria, algae, fungi, plants, insects, and vertebrates. The rhythms are supported by cell-autonomous circadian clocks, which regulate expression of a large number of genes on the level of transcription (for review, see Transcriptional/translational feedback loops are hallmarks of circadian clocks in all organisms. In eukaryotes, expression of core clock components is organized in a complex network of interconnected positive and negative feedback loops (for review, see Dunlap and Loros 2004;Gachon et al. 2004;Hardin 2005). This network of gene expression is assumed to generate circadian rhythmicity. Elimination of key components of these interconnected loops disrupts many, if not all, rhythmic outputs, depending on the organism. Expression, subcellular localization, assembly, function, and turnover of clock components are crucial for circadian rhythmicity, and thus, the core clock is embedded in a supra-net of cellular machinery regulating various aspects of clock function. Protein phosphorylation and dephosphorylation are important regulatory mechanisms that are critical for self-sustained circadian rhythmicity and entrainment of clocks to external cues. It is unclear to what extent reversible phosphorylations are mechanistically instrumental for generation of rhythmicity in eukaryotic clocks.Recent findings have shown that clock proteins in cyanobacteria generate a self-sustained circadian rhythm of autophosphorylation and dephosphorylation, which is independent of tra...

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“…Because recombinant Ub proteins that have NH 2 -terminal epitope extensions, such as His 6 -Ub, myc-Ub, and glutathione S-transferase-Ub, can substitute for wild-type Ub in a variety of Ub conjugation reactions (24 -28), there is a largely untested assumption that wild-type Ub situated at the COOH terminus will trigger the ubiquitin fusion degradation pathway, resulting in degradation of X-Ub fusions by proteasome. This issue is complicated by the conjugation of the X-Ub to target proteins via Ub Gly 76 , which is available for isopeptide bond formation (22).…”

Section: Ubiquitin (Ub)mentioning

confidence: 99%

Fusion Proteins with COOH-terminal Ubiquitin Are Stable and Maintain Dual Functionality in Vivo

Qian¹,

Ott²,

Schubert³

et al. 2002

Journal of Biological Chemistry

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The ubiquitin (Ub) fusion degradation pathway functions to degrade fusion proteins containing a nonremovable Ub moiety at their NH 2 terminus (Johnson, E. S., Ma, P. C., Ota, I. M., and Varshavsky, A. (1995) J. Biol. Chem. 270, 17442-17456). Here we show that ubiquitin fusion degradation also targets proteins for proteasomal degradation when Ub is present in the middle of fusion proteins (X-Ub-Y), in a process that entails polyubiquitylation of Ub Lys 48 . By contrast, fusion proteins bearing COOH-terminal Ub (X-Ub) are metabolically stable. Such fusion proteins, either newly biosynthesized or generated by Ub hydrolases, are reversibly conjugated to heterogeneous target proteins in a manner similar to wild-type Ub. Most importantly, the NH 2 -terminal fusion partner (X) can maintain its structure and function in the formed X-Ub conjugates as inferred from the fluorescence of green fluorescent protein-Ub conjugates and the incorporation of human immunodeficiency virus type 1 Gag-Ub into viral particles. These findings strongly suggest that 26S proteasomes exhibit spatial discrimination of Ub-conjugated proteins, sparing domains extended from the NH 2 terminus of Ub from unfolding and degradation. The multifunctionality of X-Ub fusion proteins opens the possibility for a number of novel practical applications, including the imaging of Ub conjugate formation in living cells.

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Ubiquitination of the PEST-like Endocytosis Signal of the Yeast a-Factor Receptor

Cited by 104 publications

References 40 publications

Parkin Ubiquitinates and Promotes the Degradation of RanBP2

Parkin Ubiquitinates and Promotes the Degradation of RanBP2

Transcriptional and post-transcriptional regulation of the circadian clock of cyanobacteria and Neurospora

Fusion Proteins with COOH-terminal Ubiquitin Are Stable and Maintain Dual Functionality in Vivo

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