Determinants for Dephosphorylation of the RNA Polymerase II C-Terminal Domain by Scp1

Zhang, Yan; Kim, Young‐Jun; Genoud, Nicolas; Gao, Jianmin; Kelly, Jeffery W.; Pfaff, Samuel L.; Gill, Gordon N.; Dixon, Jack E.; Noel, Joseph P.

doi:10.1016/j.molcel.2006.10.027

Cited by 107 publications

(166 citation statements)

References 57 publications

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“…HADSF enzymes with C0 cap types have been associated with histidine biosynthesis (30), inner core lipopolysaccharide biosynthesis (20), glycolipid and glycoprotein decoration for cell surface display (31,32), tRNA repair (33), and phosphoprotein phosphatase activity (23,34). As is the case with Q8A9J5 the HADSF polynucleotide phosphatases and phosphoprotein phosphatases are monomeric [in published cases Fcp1, Scp1, dullard, MDP-1, and T4 polynucleotide phosphatase/ kinase (23,(33)(34)(35)(36)], apparently allowing recognition of large polymeric (i.e., protein and nucleic acid) substrates. Steady-state kinetic assay of Q8A9J5 revealed specificity for phosphotyrosine with k cat /K m = 3. .…”

Section: Resultsmentioning

confidence: 99%

“…The substrate-leaving group structure may be limited by the necessity of acting as a barrier between bulk solvent and the active-site Mg 2+ cofactor, nucleophilic Asp, and Asp general acid/base, replacing the cap domain in this role. Indeed, structures of the C0 HADSF members Scp-1 (35) and GmhB (42) show that the fit between enzyme and substrate does not allow a probe the size of water to enter the active site (see SI Appendix, Fig. S22).…”

Section: Discussionmentioning

confidence: 99%

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Panoramic view of a superfamily of phosphatases through substrate profiling

Huang

Pandya

Liu

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

136

139

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Large-scale activity profiling of enzyme superfamilies provides information about cellular functions as well as the intrinsic binding capabilities of conserved folds. Herein, the functional space of the ubiquitous haloalkanoate dehalogenase superfamily (HADSF) was revealed by screening a customized substrate library against >200 enzymes from representative prokaryotic species, enabling inferred annotation of ∼35% of the HADSF. An extremely high level of substrate ambiguity was revealed, with the majority of HADSF enzymes using more than five substrates. Substrate profiling allowed assignment of function to previously unannotated enzymes with known structure, uncovered potential new pathways, and identified isofunctional orthologs from evolutionarily distant taxonomic groups. Intriguingly, the HADSF subfamily having the least structural elaboration of the Rossmann fold catalytic domain was the most specific, consistent with the concept that domain insertions drive the evolution of new functions and that the broad specificity observed in HADSF may be a relic of this process.evolution | specificity | phosphatase | substrate screen | promiscuity S ince the first genomes were sequenced, there has been an exponential increase in the number of protein sequences deposited into databases worldwide. At the time of this writing the UniProtKB/TrEMBL database contains over 32 million protein sequences. Although this increase in sequence data has dramatically enhanced our understanding of the genomic organization of organisms, as the number of protein sequences grows, the proportion of firm functional assignments diminishes. Traditionally, methods of functional annotation involve comparing sequence identity between experimentally characterized proteins and newly sequenced ones, typically via BLAST (1). In cases where significant sequence similarity cannot be ascertained, proteins are annotated as "hypothetical" or "putative." Moreover, the decrease in sequence identity leads to an increased uncertainty in functional assignment, especially as the phylogenetic distance between organisms grows, limiting iso-functional ortholog discovery.As the number of newly sequenced genomes grows larger, more protein sequences are likely to be misannotated, oftentimes resulting in the propagation of incorrect functional annotation across newly identified sequences. To tackle the problem of unannotated or misannotated proteins, newer methods for computational assignment have been created with varying degrees of success (2). Although these methods outperform historical methods, continued improvement is necessary to ensure accurate annotation of function (2). A greater swath of functional space can be covered by screening substrates in a high-throughput manner on multiple enzymes from a family (3, 4). Family-wide substrate profiling offers a data-rich resource. The use of sparse screening of sequence space and a diversified library permits the determination of substrate specificity profiles to provide a familywide view of the range of substrates...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Panoramic view of a superfamily of phosphatases through substrate profiling

Huang

Pandya

Liu

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

136

139

View full text Add to dashboard Cite

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“…5(A)]. 63 The Ser2-phosphorylated CTD binds to a CTD-interacting domain (CID) in protein1 of cleavage and polyadenylation factor I (PCF11), which is essential for transcription elongation 3 0 and RNA processing [ Fig. 5(B)].…”

Section: Examination Of the Morfs In Rnap II And Histone H3mentioning

confidence: 99%

Exploring the binding diversity of intrinsically disordered proteins involved in one‐to‐many binding

et al. 2013

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Molecular recognition features (MoRFs) are intrinsically disordered protein regions that bind to partners via disorder-to-order transitions. In one-to-many binding, a single MoRF binds to two or more different partners individually. MoRF-based one-to-many protein-protein interaction (PPI) examples were collected from the Protein Data Bank, yielding 23 MoRFs bound to 2-9 partners, with all pairs of same-MoRF partners having less than 25% sequence identity. Of these, 8 MoRFs were bound to 2-9 partners having completely different folds, whereas 15 MoRFs were bound to 2-5 partners having the same folds but with low sequence identities. For both types of partner variation, backbone and side chain torsion angle rotations were used to bring about the conformational changes needed to enable close fits between a single MoRF and distinct partners. Alternative splicing events (ASEs) and posttranslational modifications (PTMs) were also found to contribute to distinct partner binding. Because ASEs and PTMs both commonly occur in disordered regions, and because both ASEs and PTMs are often tissue-specific, these data suggest that MoRFs, ASEs, and PTMs may collaborate to alter PPI networks in different cell types. These data enlarge the set of carefully studied MoRFs that use inherent flexibility and that also use ASE-based and/or PTM-based surface modifications to enable the same disordered segment to selectively associate with two or more partners. The small number of residues involved in MoRFs and in their modifications by ASEs or PTMs may simplify the evolvability of signaling network diversity.

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“…Protein stability is often regulated by a balance between kinase and phosphatase activities. CTDSP1 was first identified as a nuclear phosphatase targeting the C terminus of RNA polymerase II (19)(20)(21). Subsequently it was implicated in REST repression of neuronal gene expression in P19 embryonal carcinoma cells that have the capacity to differentiate into neurons (22).…”

Section: Rest-gfp Fusion Peptides Can Be Used To Monitor Phosphorylationmentioning

confidence: 99%

C-terminal domain small phosphatase 1 and MAP kinase reciprocally control REST stability and neuronal differentiation

Nesti

Corson

McCleskey

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The repressor element 1 (RE1) silencing transcription factor (REST) in stem cells represses hundreds of genes essential to neuronal function. During neurogenesis, REST is degraded in neural progenitors to promote subsequent elaboration of a mature neuronal phenotype. Prior studies indicate that part of the degradation mechanism involves phosphorylation of two sites in the C terminus of REST that require activity of beta-transducin repeat containing E3 ubiquitin protein ligase, βTrCP. We identify a proline-directed phosphorylation motif, at serines 861/864 upstream of these sites, which is a substrate for the peptidylprolyl cis/trans isomerase, Pin1, as well as the ERK1/2 kinases. Mutation at S861/864 stabilizes REST, as does inhibition of Pin1 activity. Interestingly, we find that C-terminal domain small phosphatase 1 (CTDSP1), which is recruited by REST to neuronal genes, is present in REST immunocomplexes, dephosphorylates S861/864, and stabilizes REST. Expression of a REST peptide containing S861/864 in neural progenitors inhibits terminal neuronal differentiation. Together with previous work indicating that both REST and CTDSP1 are expressed to high levels in stem cells and down-regulated during neurogenesis, our results suggest that CTDSP1 activity stabilizes REST in stem cells and that ERK-dependent phosphorylation combined with Pin1 activity promotes REST degradation in neural progenitors.T he repressor element 1 (RE1) silencing transcription factor (REST) is a transcriptional repressor that suppresses neuronal gene expression in nonneural cells, such as fibroblasts, as well as in neural progenitors (1-3). Its targets represent genes required for the terminally differentiated neuronal cell phenotype, including genes encoding voltage and ligand-dependent ion channels, receptors, growth factors, and axonal-guidance proteins (4-7). Thus, during neurogenesis, REST is progressively down-regulated to allow elaboration of the mature neuronal phenotype (3). Nonetheless, precisely how REST itself is regulated still remains an open question. Relatively little is known about either its transcriptional or posttranscriptional regulation (3,8,9). In contrast, several studies have focused on posttranslational regulation of REST (3, 10, 11), but the identity of the signaling molecules involved has received little attention.In neural progenitors and human embryonic kidney (HEK) cells, rapid REST turnover is mediated by targeting to a proteasomal pathway (3, 10, 11). REST degradation during neuronal differentiation in culture requires interaction with beta-transducin repeat containing E3 ubiquitin protein ligase (βTrCP) for targeting to the proteasome (11). βTrCP was also required for cell-cycle-dependent degradation of REST in HEK cells (10). Two adjacent phosphorylated peptides in the C-terminal domain of REST were identified as βTrCP substrates in these studies, and function as degrons. One kinase responsible for the phosphorylation and degron activity in hippocampus is casein kinase 1, CK1 (12), but whether it function...

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Determinants for Dephosphorylation of the RNA Polymerase II C-Terminal Domain by Scp1

Cited by 107 publications

References 57 publications

Panoramic view of a superfamily of phosphatases through substrate profiling

Panoramic view of a superfamily of phosphatases through substrate profiling

Exploring the binding diversity of intrinsically disordered proteins involved in one‐to‐many binding

C-terminal domain small phosphatase 1 and MAP kinase reciprocally control REST stability and neuronal differentiation

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