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

Keywords:

• CRD4
• RMM
• 2CHO
• PCA analysis

Acknowledgments

In Brazil, this study was supported by FAPESP (Grant # 2021/11205-9). GMF is a recipient of a fellowship from FAPESP, Brazil. We acknowledge Desmond Molecular Dynamics System, version 6.4, D. E. Shaw Research, New York, NY for making this software available for academics.

Author contributions

L.A.N. and G.M.F. design in silico experiments and analysis. L.A.N., G.M.F. and E.I.F. helped with the discussion and writing. G.M.F and E.I.F contributed to resources and overall study supervision. All authors prepared and reviewed the manuscript.

Competing interests

The authors declare no competing interests.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico;Fundação de Amparo à Pesquisa do Estado de São Paulo.