Exploring the conformational dynamics of the CRD4: a model for receptor lysosomal activity shifts in search of 'sweet’ and ‘sour’ states

Abstract

The macrophage mannose receptor (RMM) is a crucial component of the immune system involved in immune responses, inflammation resolution, and tissue remodeling. When RMM is activated by a specific ligand, it undergoes internalization, forming an endosome that matures into a lysosome. Within the lysosome, structural changes in RMM facilitate the dissociation of ligands for further processing. However, the precise details of these structural changes are not well understood. In this study, we used molecular dynamics simulations to investigate the conformational dynamics of a specific region called CRD4 in RMM. Our simulations explored different conditions, including pH variations and the presence of Ca2+ ions. By analyzing the simulation data, we found that conformational changes primarily occur in loop regions, while the secondary structure remains stable. The binding site of CRD4, essential for ligand interaction, is located on the protein surface between two specific loop regions. Ligand binding is stabilized by three important amino acids. Interestingly, the interaction patterns differ between monosaccharide and disaccharide ligands. These findings improve our understanding of CRD4's dynamics and how it recognizes ligands. They provide insights into the structure of CRD4 and its role in ligand dissociation within lysosomes. The study also highlights the significance of loop regions in functional dynamics and interactions. Further research is needed to fully uncover the complete structure of CRD4, understand ligand binding modes, and explore the influence of environmental factors. This study lays the foundation for future investigations targeting carbohydrate-protein interactions and the development of therapeutics based on RMM's unique properties. Communicated by Ramaswamy H. Sarma