Abstract
DEC-205 (CD205), a member of the macrophage mannose receptor protein family, is the prototypic endocytic receptor of dendritic cells, whose ligands include phosphorothioated cytosine–guanosine oligonucleotides, a motif often seen in bacterial or viral DNA. However, despite growing biological and clinical significance, little is known about the structural arrangement of this receptor or any of its family members. Here, we describe the 3.2 Å cryo-EM structure of human DEC-205, thereby illuminating the structure of the mannose receptor protein family. The DEC-205 monomer forms a compact structure comprising two intercalated rings of C-type lectin-like domains, where the N-terminal cysteine-rich and fibronectin domains reside at the central intersection. We establish a pH-dependent oligomerization pathway forming tetrameric DEC-205 using solution-based techniques and ultimately solved the 4.9 Å cryo-EM structure of the DEC-205 tetramer to identify the unfurling of the second lectin ring which enables tetramer formation. Furthermore, we suggest the relevance of this oligomerization pathway within a cellular setting, whereby cytosine–guanosine binding appeared to disrupt this cell-surface oligomer. Accordingly, we provide insight into the structure and oligomeric assembly of the DEC-205 receptor.
Highlights
Recruitment to clathrin-coated pits and allow continuous endocytosis of exogenous cargo to the cell interior [5]
The DEC-205 monomer showed the lemniscate structure of DEC-205 ECD and macrophage mannose receptor (MR) is comprised of two intercalated rings of C-type lectin-like domains (CTLDs) with the CysR and FN domain located at the central intersect
Such structural rearrangement was directly resultant from an increase in pH, a trait observed in studies of the MR
Summary
Received for publication, October 15, 2020, and in revised form, November 23, 2020 Published, Papers in Press, November 30, 2020, https://doi.org/10.1074/jbc.RA120.016451 Benjamin S. Gully1,2,* , Hariprasad Venugopal3, Alex J. Fulcher4, Zhihui Fu1, Jessica Li1, Felix A. Deuss1 , Carmen Llerena1, William R. Heath5,6 , Mireille H. Lahoud1 , Irina Caminschi1 , Jamie Rossjohn1,2,7,* , and Richard Berry1,2,* From the 1Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, 2Australian Research Council Centre of Excellence for Advanced Molecular Imaging, 4Monash Micro Imaging, Monash University, Clayton, Victoria, Australia; 3Ramaciotti Centre for Cryo Electron Microscopy, Monash University, Melbourne, Victoria, Australia; 5Department of Microbiology and Immunology, The Peter Doherty Institute, 6Australian Research Council Centre of Excellence for Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria, Australia; and 7Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, United Kingdom
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