Barley in Minnesota

12 pages; includes photographs. This archival publication may not reflect current scientific knowledge or recommendations. Current information available from the University of Minnesota Extension: https://www.extension.umn.edu

Evaluation and extension of the two-site, two-step model for binding and activation of the chemokine receptor CCR1

© 2019 Sanchez et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc. Interactions between secreted immune proteins called chemokines and their cognate G protein– coupled receptors regulate the trafficking of leukocytes in inflammatory responses. The two-site, two-step model describes these interactions. It involves initial binding of the chemokine N-loop/3 region to the receptor’s N-terminal region and subsequent insertion of the chemokine N-terminal region into the transmembrane helical bundle of the receptor concurrent with receptor activation. Here, we test aspects of this model with C-C motif chemokine receptor 1 (CCR1) and several chemokine ligands. First, we compared the chemokine-binding affinities of CCR1 with those of peptides corresponding to the CCR1 N-terminal region. Relatively low affinities of the peptides and poor correlations between CCR1 and peptide affinities indicated that other regions of the receptor may contribute to binding affinity. Second, we evaluated the contributions of the two CCR1-interacting regions of the cognate chemokine ligand CCL7 (formerly monocyte chemoattractant protein-3 (MCP-3)) using chimeras between CCL7 and the non-cognate ligand CCL2 (formerly MCP-1). The results revealed that the chemokine N-terminal region contributes significantly to binding affinity but that differences in binding affinity do not completely account for differences in receptor activation. On the basis of these observations, we propose an elaboration of the two-site, two-step model—the “three-step” model—in which initial interactions of the first site result in low-affinity, nonspecific binding; rate-limiting engagement of the second site enables high-affinity, specific binding; and subsequent conformational rearrangement gives rise to receptor activation

Key determinants of selective binding and activation by the monocyte chemoattractant proteins at the chemokine receptor CCR2

Chemokines and their receptors collectively orchestrate the trafficking of leukocytes in normal immune function and inflammatory diseases. Different chemokines can induce distinct responses at the same receptor. In comparison to monocyte chemoattractant protein-1 (MCP-1; also known as CCL2), the chemokines MCP-2 (CCL8) and MCP-3 (CCL7) are partial agonists of their shared receptor CCR2, a key regulator of the trafficking of monocytes and macrophages that contribute to the pathology of atherosclerosis, obesity, and type 2 diabetes. Through experiments with chimeras of MCP-1 and MCP-3, we identified the chemokine amino-terminal region as being the primary determinant of both the binding and signaling selectivity of these two chemokines at CCR2. Analysis of CCR2 mutants showed that the chemokine amino terminus interacts with the major subpocket in the transmembrane helical bundle of CCR2, which is distinct fromthe interactions of some other chemokines with the minor subpockets of their receptors. These results suggest the major subpocket as a target for the development of small-molecule inhibitors of CCR2. 2017 © The Authors

French trade unions and the union of the left

SIGLEAvailable from British Library Document Supply Centre- DSC:DX86660 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

The characterisation of a Bronze Age weapon hoard

The study described here is based on the proposition that all events in the life of a bronze artefact, from the moment it was cast to the time it became available for characterisation, have the potential to leave a trace that can be identified by one or more metallographic methods. The hoard presented here was found at Waterden, Norfolk, England by metal detecting and excavation after it was scattered by the plough. The find comprises 201 fragments from approximately 130 swords and spearheads. It is important for understanding the evolution of the Bronze Age sword in Britain, and also for understanding the destruction and deposition of weapons in weapon-only assemblages. Besides a consideration of the hoard from a typological perspective the project used five methods of examination: a) a surface study for manufacturing traces, combat damage, possible cremation, and damage in the ground or at recovery, b) radiography, c) compositional analysis by electron probe microanalysis, d) optical metallography, and e) microhardness testing. This is the first occasion in which these techniques have been combined in the investigation of a complete hoard. It has been possible to divide the results from each technique into simple categories so that clear correlations can be made, so it can be shown that sword blades had more elaborate finishing than others, that some workshops had better casting practice than others and that the great majority of swords had combat damage. The effects of destruction and fire are also discussed and a context for the deposition of the hoard reconstructed

Structural basis of receptor sulfotyrosine recognition by a cc chemokine: The n-terminal region of CCR3 bound to CCL11/eotaxin-1

© 2014 Elsevier Ltd. Trafficking of leukocytes in immune surveillance and inflammatory responses is activated by chemokines engaging their receptors. Sulfation of tyrosine residues in peptides derived from the eosinophil chemokine receptor CCR3 dramatically enhances binding to cognate chemokines. We report the structural basis of this recognition and affinity enhancement. We describe the structure of a CC chemokine (CCL11/eotaxin-1) bound to a fragment of a chemokine receptor: residues 8-23 of CCR3, including two sulfotyrosine residues. We also show that intact CCR3 is sulfated and sulfation enhances receptor activity. The CCR3 sulfotyrosine residues form hydrophobic, salt bridge and cation-π interactions with residues that are highly conserved in CC chemokines. However, the orientation of the chemokine relative to the receptor N terminus differs substantially from those observed for two CXC chemokines, suggesting that initial binding of the receptor sulfotyrosine residues guides subsequent steps in receptor activation, thereby influencing the receptor conformational changes and signaling