ACS DIVISION OF BIOLOGICAL CHEMISTRY

January 8th, 2018 by Tetsuya Hori

Na⁺-mimicking ligands stabilize the inactive state of leukotriene B₄ receptor BLT1

Na⁺-mimicking ligands stabilize the inactive state of leukotriene B₄ receptor BLT1, Published online: 08 January 2018; doi:10.1038/nchembio.2547

A structure of leukotriene B4 receptor BLT1 bound with a benzamidine-containing compound, BIIL260, reveals an inverse-agonist mechanism involving ligand binding in the sodium ion-centered water cluster adjacent to the conserved orthosteric site of class A GPCRs.

January 4th, 2018 by Ganglin Wang, Zhi Li and Nan Ma

January 2nd, 2018 by Joshua H. Cook, Norikiyo Ueno, Melissa B. Lodoen

The motility of blood monocytes is orchestrated by the activity of cell surface integrins, which translate extracellular signals into cytoskeletal changes to mediate adhesion and migration. Toxoplasma gondii is an intracellular parasite that infects migratory cells and enhances their motility, but the mechanisms underlying T. gondii-induced hypermotility are incompletely understood. We have investigated the molecular basis for the hypermotility of primary human peripheral blood monocytes and THP-1 cells infected with T. gondii. Compared to uninfected monocytes, T. gondii infection of monocytes reduced cell spreading and the number of activated β1 integrin clusters in contact with fibronectin during settling, an effect not observed in monocytes treated with LPS or E. coli. Furthermore, T. gondii infection disrupted the phosphorylation of focal adhesion kinase (FAK) at tyrosine 397 (Y397) and Y925 and of the related protein proline-rich tyrosine kinase (Pyk2) at Y402. The localization of paxillin, FAK, and vinculin to focal adhesions and the colocalization of these proteins with activated β1 integrins were also impaired in T. gondii-infected monocytes. Using time-lapse confocal microscopy of THP-1 cells expressing eGFP-FAK during settling on fibronectin, we found that T. gondii-induced monocyte hypermotility was characterized by a reduced number of eGFP-FAK-containing clusters over time compared to uninfected cells. This study demonstrates an integrin conformation-independent regulation of the β1 integrin adhesion pathway, providing further insight into the molecular mechanism of T. gondii- induced monocyte hypermotility.

January 1st, 2018 by Andrea Chini

An OPR3-independent pathway uses 4,5-didehydrojasmonate for jasmonate synthesis

An OPR3-independent pathway uses 4,5-didehydrojasmonate for jasmonate synthesis, Published online: 01 January 2018; doi:10.1038/nchembio.2540

OPR3 is required to reduce the JA-Ile precursor OPDA. Analyses of JA levels in a loss-of-function opr3-3 mutant identified an OPR3-independent pathway for JA-Ile biosynthesis, based on OPDA conversion to 4,5-ddh-JA and reduction to JA by OPR2.

January 1st, 2018 by Thomas E Smith

Accessing chemical diversity from the uncultivated symbionts of small marine animals

Accessing chemical diversity from the uncultivated symbionts of small marine animals, Published online: 01 January 2018; doi:10.1038/nchembio.2537

A combination of spectroscopy, metagenomics, and synthetic biology enables the characterization of the antiviral divamides, a class of lanthipeptide natural products in which even minor changes in structure lead to different biological activities.

December 27th, 2017 by Nattapol Arunrattanamook and E. Neil G. Marsh

December 26th, 2017 by Jonathan B. Baell and J. Willem M. Nissink

December 24th, 2017 by Katumori Segawa, Sachiko Kurata, Shigekazu Nagata

Flippases are enzymes that translocate phosphatidylserine (PtdSer) and phosphatidyl- ethanolamine (PtdEtn) from the outer to the inner leaflet in the lipid bilayer of the plasma membrane, leading to the asymmetric distribution of aminophospholipids in the membrane. One mammalian phospholipid flippase at the plasma membrane is ATP11C, a type IV P-type ATPase (P4-ATPase) that forms a hetero-complex with the transmembrane protein CDC50A. However, the structural features in CDC50A that support the function of ATP11C and other P4-ATPases have not been characterized. Here, using error-prone PCR-mediated mutagenesis of human CDC50A cDNA followed by functional screening and deep sequencing, we identified 14 amino acid residues that affect ATP11C’s flippase activity. These residues were all located in CDC50A’s extracellular domain and were evolutionarily well conserved. Most of the mutations decreased CDC50A’s ability to chaperone ATP11C and other P4-ATPases to their destinations. The CDC50A mutants failed to form a stable complex with ATP11C and could not induce ATP11C’s PtdSer-dependent ATPase activity. Notably, one mutant variant could form a stable complex with ATP11C and transfer ATP11C to the plasma membrane, yet the ATP11C complexed with this CDC50A variant had very weak or little PtdSer- or PtdEtn-dependent ATPase activity. These results indicated that the extracellular domain of CDC50A has important roles both in CDC50A’s ability to chaperone ATP11C to the plasma membrane and in inducing ATP11C’s ATP hydrolysis–coupled flippase activity.

December 22nd, 2017 by Erica A. Frankel and Philip C. Bevilacqua

December 22nd, 2017 by Fredrik W. Sadler, Igor Dodevski and Casim A. Sarkar