Disease mutations in the ryanodine receptor central region: crystal structures of a phosphorylation hot spot domain

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Highlights? Crystal structures of a central RyR domain contain phosphorylation sites ? Eleven RyR1 disease mutations cluster on two opposite faces of the domain ? The RyR1 L2867G mutation causes a drastic destabilization ? In vitro phosphorylation identifies 5 PKA and 4 CaMKII targets     

Variable lymphocyte receptor recognition of the immunodominant glycoprotein of Bacillus anthracis spores

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Highlights? VLRBs use their C-terminal LRRs and the LRRCT-loop to interact with antigen ? Sequence-related VLRBs exhibit differential recognition of their BclA epitopes ? VLR4 binds a conserved protein epitope, yet is specific for B. anthracis spores     

Structure of the Pentameric Ligand-Gated Ion Channel GLIC Bound with Anesthetic Ketamine

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Highlights? The structure of ketamine-bound GLIC reveals an anesthetic binding site ? The study provides compelling evidence for allosteric inhibition by anesthetics ? Ketamine inhibition on GLIC is similar to competitive antagonist action on nAChRs ? Ketamine directly acts on pLGICs in addition to NMDA receptors     

Distinct and Overlapping Roles for AP-1 and GGAs Revealed by the “Knocksideways” System

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Highlights? AP-1 knocksideways depletes ～100 proteins from clathrin-coated vesicles (CCVs) ? GGA2 knocksideways mainly depletes hydrolases and their receptors ? GGA2 depends on AP-1 for incorporation into CCVs ? AP-1 acts as a linchpin for intracellular CCV formation and is bidirectional     

Molecular mechanism for inhibition of g protein-coupled receptor kinase 2 by a selective RNA aptamer

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Highlights? C13 RNA aptamer variants stabilize GRK2 in a unique and remodeled conformation ? The aptamer positions an adenine nucleotide into the ATP-binding pocket of GRK2 ? Basic residues on an exterior surface of GRK2 facilitate aptamer binding ? The terminal stem of the aptamer indirectly contributes to affinity     

Mixed-Linkage Ubiquitin Chains Send Mixed Messages

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Highlights? K48 and K63 linkages in branched and unbranched tri-Ub retain their structural features ? Linkage-selective receptors recognize K48 and K63 linkages in the branched tri-Ub ? Linkage-specific deubiquitinases cleave their cognate Ub-Ub linkages in the mixed-linkage chains ? The 26S proteasome recognizes and processes branched K48- and K63-linked tri-Ub     

LRP6 Enhances Glucose Metabolism by Promoting TCF7L2-Dependent Insulin Receptor Expression and IGF Receptor Stabilization in Humans

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Highlights? Nondiabetic LRP6 mutation carriers are hyperinsulinemic and insulin resistant ? IR expression is reduced in skeletal muscles of the LRP6 mutation carriers ? Wnt/LRP6 regulate the insulin receptor and IGFR expression ? The LRP6 mutation reduces TCF7L2-dependent IR expression and enhances mTOR activity     

HnRNP L and HnRNP A1 Induce Extended U1 snRNA Interactions with an Exon to Repress Spliceosome Assembly

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Highlights? HnRNP L recruits hnRNP A1 and U1 snRNA to sequences upstream of the 5′ splice site ? HnRNP L-induced extended base pairing of U1 snRNA inhibits exchange for U6 snRNA ? Local traps in spliceosome assembly are naturally exploited mechanisms of regulation ? Extended base pairing of U1 may account for much of regulation by hnRNPs L and A1     

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     

Leukemia Fusion Target AF9 Is an Intrinsically Disordered Transcriptional Regulator that Recruits Multiple Partners via Coupled Folding and Binding

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Highlights? The AF9 AHD is intrinsically disordered ? The AHD recruits AF4, BCoR, Dot1L, and hPC3 by coupled folding and binding ? AF9 binding partners compete for binding to a common site ? Dynamics of the AF4-AF9 complex may facilitate exchange between partners     

Structure and 3D Arrangement of Endoplasmic Reticulum Membrane-Associated Ribosomes

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Highlights? Subtomogram average of the canine ER-associated ribosome in situ at 31 Å resolution ? Large subunit rRNA ES27L is in direct contact with the ER membrane ? Sec61, TRAP, and potentially OST and the SP complex are resolved ? ER-associated ribosomes adopt a preferred arrangement, likely polyribosome specific     

Mycobacterium tuberculosis activates the DNA-dependent cytosolic surveillance pathway within macrophages

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Highlights? M. tuberculosis permeabilizes phagosomes and activates cytosolic signaling pathways ? Host cytoplasmic DNA receptors sense M. tuberculosis extracellular DNA ? DNA recognition activates the STING/TBK1/IRF3 pathway ? Cytosolic sensing promotes M. tuberculosis infection     

Differential Regulation of Distinct Vps34 Complexes by AMPK in Nutrient Stress and Autophagy

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Highlights? Different Vps34 complexes are distinctly regulated upon energy stress ? AMPK activates the proautophagy Vps34 complex by phosphorylating Beclin1 ? AMPK inhibits the nonautophagic Vps34 complex by phosphorylating Vps34 ? ATG14L determines whether the Vps34 complex is activated or inhibited by AMPK     

Supertertiary Structure of the MAGUK Core from PSD-95

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Highlights? Using NMR and SAXS, we depict the dynamic structure of the MAGUK core PSD-95 ? PDZ3 of the MAGUK core interacts with SH3 via its canonical peptide binding groove ? Binding of PDZ peptides, such as CRIPT, disrupts the interaction between PDZ3 and SH3 ? Rosetta modeling shows that linker residues L411/M412 dock into the PDZ3 binding site     

Deprotonation of D96 in Bacteriorhodopsin Opens the Proton Uptake Pathway

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Highlights? The X-ray crystal structure of the D96G/F171C/F219L of bR is presented ? MD simulation show that deprotonation of D96 opens the cytoplasmic side ? Hydration of the cytoplasmic side is influenced by the protonation state of D96     

The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways

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Highlights? PGAM5 is a mitochondrial phosphatase that functions in programmed necrosis (necroptosis) ? Both splicing variants of PGAM5, PGAM5L and PGAM5S, are required for necroptosis ? PGAM5 dephosphorylates and activates mitochondrial fission protein Drp1 ? PGAM5 is required for necrosis induced by TNF-α, ROS, and calcium overload     

Legionella pneumophila Effector RomA Uniquely Modifies Host Chromatin to Repress Gene Expression and Promote Intracellular Bacterial Replication

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Highlights? Upon infection, L. pneumophila secretes RomA, a SET domain-containing methyltransferase ? RomA triggers H3K14 trimethylation, causing a switch from gene activation to repression ? ChIP-seq identified 4,870 H3K14 methylated promoter regions, including innate immune genes ? RomA SET domain is required for efficient intracellular replication of L. pneumophila     

SIP1 Mediates Cell-Fate Decisions between Neuroectoderm and Mesendoderm in Human Pluripotent Stem Cells

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Highlights? Smad-interacting protein 1 (SIP1) regulates hESC differentiation ? SIP1 upregulation promotes neuroectodermal differentiation ? SIP1 inhibits mesendodermal and endodermal differentiation ? SMAD2/3 and NANOG/OCT4/SOX2 cooperatively regulate SIP1 expression     

Keeping cell identity in Arabidopsis requires PRC1 RING-finger homologs that catalyze H2A monoubiquitination

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Highlights? AtBMI1A/B proteins prevent misexpression of embryonic traits in somatic cells ? PRC2 and AtBMI1A/B proteins maintain cells in their differentiated state ? AtBMI1A/B proteins mediate H2A monoubiquitination