Journal of Biological Chemistry
Volume 296, January–June 2021, 100127
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Research Article
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The cryo-EM structure of the endocytic receptor DEC-205

https://doi.org/10.1074/jbc.RA120.016451Get rights and content
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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.

Keywords

immunology
cryo-electron microscopy
receptor structure function
oligomerization
membrane protein
receptor endocytosis
dendritic cell

Abbreviations

CpG
cytosine–guanosine
CTLDs
C-type lectin-like domains
CysR
cysteine-rich
DCs
dendritic cells
ECDs
ectodomains
eGFP
enhanced green fluorescent protein
FNII
fibronectin type II
MR
mannose receptor
PLA2R
M-type phospholipase A2 receptor
SEC-MALS
size exclusion–coupled multiangle light scattering
SV-AUC
sedimentation velocity analytical ultracentrifugation

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Benjamin Gully is a postdoctoral researcher and team leader within the Rossjohn Laboratory at the Monash Biomedicine Discovery Institute. His research investigates the paradigms of immune cell activation, including dendritic cells and gamma delta T-cells. By understanding these molecular events they are building a clearer picture of their functional roles in disease. Here they elucidated the structure of a dendritic cell receptor implicated in antigen uptake, a key step for T-cell surveillance. For more information please see @benjaminsgully twitter and https://research.monash.edu/en/persons/ben-gully.

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