Lymphotactin (Ltn), involved in white blood cell activation, represents a new cl

Question

Lymphotactin (Ltn), involved in white blood cell activation, represents a new class of proteins known as ‘metamorphic proteins’. Ltn exists in two very different structures that are in thermal equilibrium: conformation Ltn40 exists as a dimer made up of all beta-strands and binds glycosaminoglycans (GAGs), and conformation Ltn10 exists as a monomer, contains an beta-helix and activates G-protein coupled receptors (GPCRs). Both conformations are needed for the biological function of Ltn. (11 points) a. Taking into account that the dimer in Ltn40 is stabilized by an intermolecular salt bridge (Lys25- Glu31), why might the Ltn10 conformation be favored under high salt concentrations? (6) b. Sketch a two-dimensional conformational energy landscape diagram for Ltn in its ligand-free state (i.e. protein is not bound to GAG, GPCR, etc.). (5)

Explanation / Answer

A. Proteins with low overall charge show less effect to salt concentration and Protein with High charge are senstitive to high salt concentrat. Lymphotactin belongs to the chemokine group38–40that is regulated by proinflammatory or infectious stimuli. Ltn10-Ltn40 equilibrium could be shifted by adjusting solution conditions . For instance, in conditions of high salt and low temperature , the Ltn10 chemokine fold is exclusively populated, while at high temperature with no salt , the alternate Ltn40 -strand configuration is strongly favored. Ltn is rich in basic amino acids.Because the protein carries a net positive charge, it is likely that electrostatic interactions contribute to salt dependence of the Ltn10.  molecular dynamic (MD) simulation that investigated the effect of salt concentration on Ltn10 structural stability revealed a chloride ion persistently associated with the Arg23 and Arg43 side chains as well as backbone amides within the 40’s-loop .these observations suggest that coulombic forces contribute to metamorphic rearrangements in Ltn.we use a combination of equilibrium unfolding, NMR binding, and kinetic exchange measurements to quantify the changes in Ltn free energy associated with an increased ionic environment and mutation.interactions between Arg23 and Arg43 have a destabilizing effect on Ltn10 free energy that can be overcome by increasing the ionic strength of the surroundings.

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