ABSTRACT
The addition of polysialic acid to N- and/or O-linked glycans, referred to as polysialylation, is a rare posttranslational modification that is mainly known to control the developmental plasticity of the nervous system. Here we show that CCR7, the central chemokine receptor controlling immune cell trafficking to secondary lymphatic organs, carries polysialic acid. This modification is essential for the recognition of the CCR7 ligand CCL21. As a consequence, dendritic cell trafficking is abrogated in polysialyltransferase-deficient mice, manifesting as disturbed lymph node homeostasis and unresponsiveness to inflammatory stimuli. Structure-function analysis of chemokine-receptor interactions reveals that CCL21 adopts an autoinhibited conformation, which is released upon interaction with polysialic acid. Thus, we describe a glycosylation-mediated immune cell trafficking disorder and its mechanistic basis.
Subject(s)
Chemokine CCL21/metabolism , Chemotaxis , Dendritic Cells/physiology , Lymph Nodes/physiology , Protein Processing, Post-Translational , Receptors, CCR7/metabolism , Sialic Acids/metabolism , Animals , Bone Marrow Cells/physiology , Glycosylation , Ligands , Lymph Nodes/cytology , Mice , Mice, Inbred C57BL , Mice, Mutant StrainsABSTRACT
CCL19 and CCL21 are chemokines involved in the trafficking of immune cells, particularly within the lymphatic system, through activation of CCR7. Concurrent expression of PSGL-1 and CCR7 in naive T-cells enhances recruitment of these cells to secondary lymphoid organs by CCL19 and CCL21. Here the solution structure of CCL19 is reported. It contains a canonical chemokine domain. Chemical shift mapping shows the N-termini of PSGL-1 and CCR7 have overlapping binding sites for CCL19 and binding is competitive. Implications for the mechanism of PSGL-1's enhancement of resting T-cell recruitment are discussed.
Subject(s)
Chemokine CCL19/chemistry , Chemokine CCL19/metabolism , Membrane Glycoproteins/metabolism , Receptors, CCR7/metabolism , Binding Sites , Humans , Models, Molecular , Protein ConformationABSTRACT
Kansas State University converted its introductory biology course, previously taught as an audio-tutorial (A-T), to a studio format in 1997. We share with others information about the process involved and present assessment data for the studio format course that address 1) student exam performance in A-T and studio; 2) student course grades in A-T and studio; 3) student and instructor perceptions and attitudes for A-T and studio; 4) student performance in subsequent biology courses for A-T and studio; and 5) gains in student learning for the studio course and other traditional lecture/lab courses. Collectively, these measures demonstrate that the studio format is as effective as or more effective (for some measures) than the A-T approach and traditional approaches in providing an effective learning environment. We discuss the issues involved in comparing course formats.
