Intrinsic disorder and coiled‐coil formation in prostate apoptosis response factor 4

Libich, David S.; Schwalbe, Martin; Kate, Sachin; Venugopal, Hariprasad; Claridge, Jolyon K.; Edwards, Patrick J. B.; Dutta, Kaushik; Pascal, Steven M.

doi:10.1111/j.1742-4658.2009.07087.x

Cited by 26 publications

(39 citation statements)

References 104 publications

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“…hPar-4 (59–77) is largely unstructured in aqueous solution, consistent with predictions and experimental data for the full-length protein 22 . This is evident from the 1 H – 15 N heteronuclear single quantum coherence (HSQC) spectrum that shows limited peak dispersion in the 1 H dimension (Fig.…”

Section: Resultssupporting

confidence: 84%

Structural Basis for Par-4 Recognition by the SPRY Domain- and SOCS Box-Containing Proteins SPSB1, SPSB2, and SPSB4

Filippakopoulos

Low

Sharpe

et al. 2010

Journal of Molecular Biology

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The mammalian SPRY domain- and SOCS box-containing proteins, SPSB1 to SPSB4, belong to the SOCS box family of E3 ubiquitin ligases. Substrate recognition sites for the SPRY domain are identified only for human Par-4 (ELNNNL) and for the Drosophila orthologue GUSTAVUS binding to the DEAD-box RNA helicase VASA (DINNNN). To further investigate this consensus motif, we determined the crystal structures of SPSB1, SPSB2, and SPSB4, as well as their binding modes and affinities for both Par-4 and VASA. Mutation of each of the three Asn residues in Par-4 abrogated binding to all three SPSB proteins, while changing EL to DI enhanced binding. By comparison to SPSB1 and SPSB4, the more divergent protein SPSB2 showed only weak binding to Par-4 and was hypersensitive to DI substitution. Par-4(59–77) binding perturbed NMR resonances from a number of SPSB2 residues flanking the ELNNN binding site, including loop D, which binds the EL/DI sequence. Although interactions with the consensus peptide motif were conserved in all structures, flanking sites in SPSB2 were identified as sites of structural change. These structural changes limit high-affinity interactions for SPSB2 to aspartate-containing sequences, whereas SPSB1 and SPSB4 bind strongly to both Par-4 and VASA peptides.

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Section: Resultssupporting

confidence: 84%

Structural Basis for Par-4 Recognition by the SPRY Domain- and SOCS Box-Containing Proteins SPSB1, SPSB2, and SPSB4

Filippakopoulos

Low

Sharpe

et al. 2010

Journal of Molecular Biology

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“…Although large-scale proteomics in cells have shown that caspases cut hundreds of proteins generally at a single site, only a few proteins, such as Bid, p28 Bap31, RIP-1, osteopontin and CYLD are reported as caspase-8 substrates [30-34]. The tumor suppressor protein PAR-4 predominantly comprises an intrinsically disordered protein, with ordered segments in the C-terminal domains of the protein [35]. In this study we demonstrate that caspase-8 cleaves PAR-4 after Asp 131, thereby separating the unstructured N-terminus from the C-terminal part, which includes the NLS-containing SAC domain and the leucine zipper.…”

Section: Discussionmentioning

confidence: 99%

Caspase-8-mediated PAR-4 cleavage is required for TNFα-induced apoptosis

et al. 2014

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The tumor suppressor protein prostate apoptosis response-4 (PAR-4) is silenced in a subset of human cancers and its down-regulation serves as a mechanism for cancer cell survival following chemotherapy. PAR-4 re-expression selectively causes apoptosis in cancer cells but how its pro-apoptotic functions are controlled and executed precisely is currently unknown. We demonstrate here that UV-induced apoptosis results in a rapid caspase-dependent PAR-4 cleavage at EEPD131G, a sequence that was preferentially recognized by caspase-8. To investigate the effect on cell growth for this cleavage event we established stable cell lines that express wild-type-PAR-4 or the caspase cleavage resistant mutant PAR-4 D131G under the control of a doxycycline-inducible promoter. Induction of the wild-type protein but not the mutant interfered with cell proliferation, predominantly through induction of apoptosis. We further demonstrate that TNFα-induced apoptosis leads to caspase-8-dependent PAR-4-cleavage followed by nuclear accumulation of the C-terminal PAR-4 (132-340) fragment, which then induces apoptosis. Taken together, our results indicate that the mechanism by which PAR-4 orchestrates the apoptotic process requires cleavage by caspase-8.

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“…48 NMR analysis revealed that an important regulator of proliferation and apoptosis, cAMPresponsive (CRE)-binding (CREB) protein (CBP), contains an intrinsically disordered ACTR-binding domain (residues 2059-2117) that completely folds upon binding. 49 Combined experimental and computational analysis revealed that N-and C-terminal regions of the human Nogo proteins 50 and C-terminal domain of a mitochondrial pro-apoptotic protein ARTS 51 are typical IDPRs, and that the prostate apoptosis response factor-4 (PAR-4), 52 prostate-associated gene 4 (PAGE4) protein, 53 and important oncoprotein c-Myc 54 are mostly disordered apoptosis-related proteins.…”

Section: Discussionmentioning

confidence: 99%

Resilience of death: intrinsic disorder in proteins involved in the programmed cell death

et al. 2013

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It is recognized now that intrinsically disordered proteins (IDPs), which do not have unique 3D structures as a whole or in noticeable parts, constitute a significant fraction of any given proteome. IDPs are characterized by an astonishing structural and functional diversity that defines their ability to be universal regulators of various cellular pathways. Programmed cell death (PCD) is one of the most intricate cellular processes where the cell uses specialized cellular machinery and intracellular programs to kill itself. This cell-suicide mechanism enables metazoans to control cell numbers and to eliminate cells that threaten the animal's survival. PCD includes several specific modules, such as apoptosis, autophagy, and programmed necrosis (necroptosis). These modules are not only tightly regulated but also intimately interconnected and are jointly controlled via a complex set of protein-protein interactions. To understand the role of the intrinsic disorder in controlling and regulating the PCD, several large sets of PCD-related proteins across 28 species were analyzed using a wide array of modern bioinformatics tools. This study indicates that the intrinsic disorder phenomenon has to be taken into consideration to generate a complete picture of the interconnected processes, pathways, and modules that determine the essence of the PCD. We demonstrate that proteins involved in regulation and execution of PCD possess substantial amount of intrinsic disorder. We annotate functional roles of disorder across and within apoptosis, autophagy, and necroptosis processes. Disordered regions are shown to be implemented in a number of crucial functions, such as protein-protein interactions, interactions with other partners including nucleic acids and other ligands, are enriched in post-translational modification sites, and are characterized by specific evolutionary patterns. We mapped the disorder into an integrated network of PCD pathways and into the interactomes of selected proteins that are involved in the p53-mediated apoptotic signaling pathway.

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Intrinsic disorder and coiled‐coil formation in prostate apoptosis response factor 4

Cited by 26 publications

References 104 publications

Structural Basis for Par-4 Recognition by the SPRY Domain- and SOCS Box-Containing Proteins SPSB1, SPSB2, and SPSB4

Structural Basis for Par-4 Recognition by the SPRY Domain- and SOCS Box-Containing Proteins SPSB1, SPSB2, and SPSB4

Caspase-8-mediated PAR-4 cleavage is required for TNFα-induced apoptosis

Resilience of death: intrinsic disorder in proteins involved in the programmed cell death

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