A DNA-Damage Selective Role for BRCA1 E3 Ligase in Claspin Ubiquitylation,CHK1 Activation,and DNA Repair

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Highlights? BRCA1 E3 ligase activity is essential for a subset of DNA damage responses ? BRCA1 V26A mutant cells are sensitive to topoisomerase inhibitors but not mitomycin C ? BRCA1 selectively ubiquitylates claspin after topoisomerase inhibition ? BRCA1 E3 ligase inactivation selectively impairs CHK1 activation     

Adaptation of Aminoacyl-tRNA Synthetase Catalytic Core to Carrier Protein Aminoacylation

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Highlights? The crystal structure of the aa:CP ligase in complex with carrier protein was solved ? The interaction relies on the idiosyncratic α-helix of the aa:CP ligase ? The complex represents a unique mode of carrier protein recognition and binding ? The mechanism of amino acid attachment to carrier protein is discussed     

Structure of the Catalytic Region of DNA Ligase IV in Complex with an Artemis Fragment Sheds Light on Double-Strand Break Repair

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Highlights? The crystal structure of the DNA ligase IV/Artemis complex was solved at 2.4 Å ? The structure of DNA ligase IV (residues 1–609) shows inserts ? An Artemis helix forms a three-helix bundle with two helices from DNA ligase IV ? The structure provides insights into the mutations causing LIG4 syndrome     

CRL1-FBXO11 Promotes Cdt2 Ubiquitylation and Degradation and Regulates Pr-Set7/Set8-Mediated Cellular Migration

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Highlights? Cullin 4A promotes the autoubiquitylation of Cdt2, a substrate adaptor of CRL4^Cdt2 ? CRL1^FBXO11 also ubiquitylates and promotes the degradation of Cdt2 ? FBXO11 degrades Cdt2 to stabilize Set8 and regulate the response to TGF-β ? FBXO11 is similarly required to stabilize Set8 and promote cell migration     

Regulation of the CRL4Cdt2 Ubiquitin Ligase and Cell-Cycle Exit by the SCFFbxo11 Ubiquitin Ligase

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Highlights? FBXO11 targets CDT2, a CRL4 substrate receptor, for proteasomal degradation ? CDK-mediated phosphorylation of CDT2 degron inhibits recognition by FBXO11 ? FBXO11-mediated degradation of CDT2 controls the timing of cell-cycle exit ? FBXO11-CDT2 functional interaction is evolutionary conserved from worms to humans     

c-Cbl-Mediated Neddylation Antagonizes Ubiquitination and Degradation of the TGF-β Type II Receptor

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Highlights? c-Cbl is a NEDD8 E3 ligase of TβRII ? c-Cbl neddylates TβRII at Lys556 and Lys567 ? Neddylation stabilizes TβRII by regulating receptor endocytic routes ? Aberrant neddylation of TβRII is associated with leukemia     

Promiscuous Interactions of gp78 E3 Ligase CUE Domain with Polyubiquitin Chains

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Highlights? The ubiquitin ligase gp78 recruits ubiquitinated substrates via its CUE domain ? gp78CUE:Ub complex reveals a large set of specific interactions ? gp78CUE binds to both distal and proximal moities of diubiquitin in a similar fashion ? The gp78CUE domain binds to K48- and K63-linked diubiquitin equally well     

IKKε-Mediated Tumorigenesis Requires K63-Linked Polyubiquitination by a cIAP1/cIAP2/TRAF2 E3 Ubiquitin Ligase Complex

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Highlights? K63-linked ubiquitination regulates IKKε innate immune and oncogenic functions ? IKKε is ubiquitinated on K30, K401, and K416 ? Ubiquitination of K30 and K401 is essential for IKKε activity and oncogene function ? A cIAP1/cIAP2/TRAF2 E3 ubiquitin ligase complex binds to and modifies IKKε     

Structural Basis of Selective Ubiquitination of TRF1 by SCFFbx4

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Highlights? SCF ubiquitin ligase subunit Fbx4 binds TRF1 using an atypical small GTPase fold ? Fbx4 recognizes a globular domain of TRF1, not just short phosphorylated degrons ? Telomere shelterin component TIN2 competes with Fbx4 for TRF1 binding ? TIN2 and SCF^Fbx4 thus control TRF1 ubiquitination and degradation     

Proteostasis Modulators Prolong Missense VHL Protein Activity and Halt Tumor Progression

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Highlights? Loss of mutant pVHL in VHL-associated tumors is due to rapid degradation ? Mutant pVHL maintains its intrinsic function as an E3 ligase ? HDACIs stabilize mutant pVHL and ameliorate tumor growth in vivo ? HDACIs represent a targeted therapy for VHL-associated tumors     

Aurora B regulates formin mDia3 in achieving metaphase chromosome alignment

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Highlights? Involvement of formin mDia3 in stable kinetochore microtubule attachment ? The actin activity of mDia3 is not necessary for metaphase chromosome alignment ? EB1-binding by mDia3 contributes to position chromosomes at the metaphase plate ? Aurora B phosphorylates mDia3 to regulate its microtubule activity     

Substrate recognition mechanism of atypical protein kinase Cs revealed by the structure of PKCι in complex with a substrate peptide from Par-3

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Highlights? The 3D structure of PKCι in complex with a peptide from Par-3 is determined ? PKCι does not need phosphorylation of Thr402 in its activation loop for its activity ? aPKCs do not need a priming kinase for their activations ? The PKCι/Par-3 structure reveals a unique substrate recognition patterns for aPKCs     

BLOC-3 Mutated in Hermansky-Pudlak Syndrome Is a Rab32/38 Guanine Nucleotide Exchange Factor

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Highlights? The Hps1-Hps4 complex (BLOC-3) is a guanine nucleotide exchange factor (GEF) ? Purified BLOC-3 has specific GEF activity toward Rab32 and Rab38 ? BLOC-3 can promote recruitment of Rab32 and Rab38 to membranes ? BLOC-3 and its target Rabs act in the biogenesis of melanosomes     

Structural Basis for the Versatile Interactions of Smad7 with Regulator WW Domains in TGF-β Pathways

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Highlights? HECT ubiquitin ligases and YAP use single or multiple WW domains to select Smad protein targets ? The targets can require multiple binding sites (R-Smads) or unique sites (ISmads) ? Binding sites are phosphorylation dependent (R-Smads) or independent (ISmad) ? Smurf1 WW1-homodimers can stabilize the close and inactive conformation of the ligase     

Hypothalamic mTORC1 Signaling Controls Sympathetic Nerve Activity and Arterial Pressure and Mediates Leptin Effects

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Highlights? Activation of hypothalamic mTORC1 increases sympathetic traffic and arterial pressure ? The sympathetic and hemodynamic effects of leptin require hypothalamic mTORC1 ? PI3K links the leptin receptor to mTORC1 signaling in the hypothalamus ? Modulating PI3K activity perturbs the sympathetic and hemodynamic functions     

A Fasting-Responsive Signaling Pathway that Extends Life Span in C. elegans

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Highlights? JNK/AP-1 signaling and DAF-16 play a central role in fasting-stimulus responses ? AP-1 and DAF-16 mediate induction of fasting genes that play key roles in life-span extension ? The SCF E3 ubiquitin ligase complex is a target of fasting-responsive signaling ? Fasting enhances protein ubiquitination, causing a reduction in protein carbonylation     

Perivascular Nitric Oxide Activates Notch Signaling and Promotes Stem-like Character in PDGF-Induced Glioma Cells

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Highlights? Perivascular niche nitric oxide activates Notch in PDGF-induced gliomas ? Notch signaling drives tumor stem-like characteristics and reduces survival ? Loss of eNOS activity decreases tumor stem-like characteristics ? Suppressing eNOS activity prolongs survival in glioma-bearing mice     

Unilateral Dampening of Bmp Activity by Nodal Generates Cardiac Left-Right Asymmetry

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Highlights? Cardiac laterality involves Nodal modulating an antimotogenic Bmp activity ? The Nodal target Hyaluronan synthase 2 unilaterally dampens Bmp signaling activity ? Nonmuscle myosin II is positively regulated by Bmp within cardiac tissue ? High levels of nonmuscle myosin II activity reduce cardiac cell motility     

ASH2L Regulates Ubiquitylation Signaling to MLL: trans-Regulation of H3 K4 Methylation in Higher Eukaryotes

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Highlights? ASH2L WH motif is important for trans-regulation of H3 K4 methylation by H2Bub ? Ub stimulates MLL activity in trans, in contrast to DOT1L regulation by H2Bub ? H2Bub enhances MLL, but not MLL3, methyltransferase activity ? H2Aub directly represses MLL methyltransferase activity     

LSD2/KDM1B and Its Cofactor NPAC/GLYR1 Endow a Structural and Molecular Model for Regulation of H3K4 Demethylation

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Highlights? Identifying NPAC as a novel LSD2 cofactor stimulating H3K4 demethylation ? Structure determination of LSD2 alone or in complex with NPAC and histone H3 peptide ? Defining the key NPAC residues essential for its intrinsic LSD2 cofactor activity ? Establishing a molecular model for how a cofactor regulates histone demethylation