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Your search keyword '"Jukes-Jones R"' showing total 2 results
Start Over Author "Jukes-Jones R" Journal nature communications
2 results on '"Jukes-Jones R"'

1. Cryo-EM structural analysis of FADD:Caspase-8 complexes defines the catalytic dimer architecture for co-ordinated control of cell fate.

Author

Fox JL, Hughes MA, Meng X, Sarnowska NA, Powley IR, Jukes-Jones R, Dinsdale D, Ragan TJ, Fairall L, Schwabe JWR, Morone N, Cain K, and MacFarlane M

Subjects
CASP8 and FADD-Like Apoptosis Regulating Protein genetics, CASP8 and FADD-Like Apoptosis Regulating Protein metabolism, Caspase 8 genetics, Caspase 8 metabolism, Catalytic Domain, Cloning, Molecular, Cryoelectron Microscopy, Death Domain Receptor Signaling Adaptor Proteins chemistry, Death Domain Receptor Signaling Adaptor Proteins genetics, Death Domain Receptor Signaling Adaptor Proteins metabolism, Escherichia coli genetics, Escherichia coli metabolism, Fas-Associated Death Domain Protein genetics, Fas-Associated Death Domain Protein metabolism, Gene Expression, Genetic Vectors chemistry, Genetic Vectors metabolism, HEK293 Cells, Humans, Models, Molecular, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, Protein Isoforms chemistry, Protein Isoforms genetics, Protein Isoforms metabolism, Protein Multimerization, Receptor-Interacting Protein Serine-Threonine Kinases genetics, Receptor-Interacting Protein Serine-Threonine Kinases metabolism, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins metabolism, Regulated Cell Death genetics, Tumor Necrosis Factor-alpha chemistry, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha metabolism, CASP8 and FADD-Like Apoptosis Regulating Protein chemistry, Caspase 8 chemistry, Fas-Associated Death Domain Protein chemistry, Receptor-Interacting Protein Serine-Threonine Kinases chemistry
Abstract

Regulated cell death is essential in development and cellular homeostasis. Multi-protein platforms, including the Death-Inducing Signaling Complex (DISC), co-ordinate cell fate via a core FADD:Caspase-8 complex and its regulatory partners, such as the cell death inhibitor c-FLIP. Here, using electron microscopy, we visualize full-length procaspase-8 in complex with FADD. Our structural analysis now reveals how the FADD-nucleated tandem death effector domain (tDED) helical filament is required to orientate the procaspase-8 catalytic domains, enabling their activation via anti-parallel dimerization. Strikingly, recruitment of c-FLIP S into this complex inhibits Caspase-8 activity by altering tDED triple helix architecture, resulting in steric hindrance of the canonical tDED Type I binding site. This prevents both Caspase-8 catalytic domain assembly and tDED helical filament elongation. Our findings reveal how the plasticity, composition and architecture of the core FADD:Caspase-8 complex critically defines life/death decisions not only via the DISC, but across multiple key signaling platforms including TNF complex II, the ripoptosome, and RIPK1/RIPK3 necrosome.

Published
2021
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2. PAXX and its paralogs synergistically direct DNA polymerase λ activity in DNA repair.

Author

Craxton A, Munnur D, Jukes-Jones R, Skalka G, Langlais C, Cain K, and Malewicz M

Subjects
Cell Line, Tumor, Chromatography, High Pressure Liquid, DNA Breaks, Double-Stranded radiation effects, DNA Repair Enzymes genetics, DNA Repair Enzymes isolation & purification, DNA-Binding Proteins genetics, DNA-Binding Proteins isolation & purification, DNA-Directed DNA Polymerase genetics, DNA-Directed DNA Polymerase isolation & purification, HEK293 Cells, Humans, Lasers adverse effects, Mutagenesis, Site-Directed, Protein Binding physiology, Protein Domains physiology, Protein Interaction Mapping methods, Protein Interaction Maps physiology, Recombinant Proteins genetics, Recombinant Proteins isolation & purification, Recombinant Proteins metabolism, Tandem Mass Spectrometry methods, DNA End-Joining Repair physiology, DNA Repair Enzymes metabolism, DNA-Binding Proteins metabolism, DNA-Directed DNA Polymerase metabolism
Abstract

PAXX is a recently identified component of the nonhomologous end joining (NHEJ) DNA repair pathway. The molecular mechanisms of PAXX action remain largely unclear. Here we characterise the interactomes of PAXX and its paralogs, XLF and XRCC4, to show that these factors share the ability to interact with DNA polymerase λ (Pol λ), stimulate its activity and are required for recruitment of Pol λ to laser-induced DNA damage sites. Stimulation of Pol λ activity by XRCC4 paralogs requires a direct interaction between the SP/8 kDa domain of Pol λ and their N-terminal head domains to facilitate recognition of the 5' end of substrate gaps. Furthermore, PAXX and XLF collaborate with Pol λ to promote joining of incompatible DNA ends and are redundant in supporting Pol λ function in vivo. Our findings identify Pol λ as a novel downstream effector of PAXX function and show XRCC4 paralogs act in synergy to regulate polymerase activity in NHEJ.

Published
2018
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