Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have identified a polypeptide that was already known to interact with polyglutamine-tract-binding protein (PQBP)-1/Npw38 as a novel splicing factor and interactor of protein phosphatase-1, hence the name SIPP1 for splicing factor that interacts with PQBP-1 and PP1 (protein phosphotase 1). SIPP1 was inhibitory to PP1, and its inhibitory potency was increased by phosphorylation with protein kinase CK1. Two-hybrid and co-sedimentation analysis revealed that SIPP1 has two distinct PP1-binding domains and that the binding of SIPP1 with PP1 involves a RVXF (Arg-Val-Xaa-Phe) motif, which functions as a PP1-binding sequence in most interactors of PP1. Enhanced-green-fluorescent-protein-tagged SIPP1 was targeted exclusively to the nucleus and was enriched in the nuclear speckles, which represent storage/assembly sites of splicing factors. We have mapped a nuclear localization signal in the N-terminus of SIPP1, while the proline-rich C-terminal domain appeared to be required for its subnuclear targeting to the speckles. Finally, we found that SIPP1 is also a component of the spliceosomes and that a SIPP1-fragment inhibits splicing catalysis by nuclear extracts independent of its ability to interact with PP1.
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PMID:SIPP1, a novel pre-mRNA splicing factor and interactor of protein phosphatase-1. 1464 Sep 81

The filovirus Ebola (EBOV) causes the most severe hemorrhagic fever known. The EBOV RNA-dependent polymerase complex includes a filovirus-specific VP30, which is critical for the transcriptional but not replication activity of EBOV polymerase; to support transcription, VP30 must be in a dephosphorylated form. Here we show that EBOV VP30 is phosphorylated not only at the N-terminal serine clusters identified previously but also at the threonine residues at positions 143 and 146. We also show that host cell protein phosphatase 1 (PP1) controls VP30 dephosphorylation because expression of a PP1-binding peptide cdNIPP1 increased VP30 phosphorylation. Moreover, targeting PP1 mRNA by shRNA resulted in the overexpression of SIPP1, a cytoplasm-shuttling regulatory subunit of PP1, and increased EBOV transcription, suggesting that cytoplasmic accumulation of PP1 induces EBOV transcription. Furthermore, we developed a small molecule compound, 1E7-03, that targeted a non-catalytic site of PP1 and increased VP30 dephosphorylation. The compound inhibited the transcription but increased replication of the viral genome and completely suppressed replication of EBOV in cultured cells. Finally, mutations of Thr(143) and Thr(146) of VP30 significantly inhibited EBOV transcription and strongly induced VP30 phosphorylation in the N-terminal Ser residues 29-46, suggesting a novel mechanism of regulation of VP30 phosphorylation. Our findings suggest that targeting PP1 with small molecules is a feasible approach to achieve dysregulation of the EBOV polymerase activity. This novel approach may be used for the development of antivirals against EBOV and other filovirus species.
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PMID:Role of protein phosphatase 1 in dephosphorylation of Ebola virus VP30 protein and its targeting for the inhibition of viral transcription. 2493 58