A pH- and ionic strength-dependent conformational change in the neck region regulates DNGR-1 function in dendritic cells.

Abstract

DNGR-1 is receptor expressed by certain dendritic cell (DC) subsets and by DC precursors in mouse. It possesses a C-type lectin-like domain (CTLD) followed by a poorly characterized neck region coupled to a transmembrane region and short intracellular tail. The CTLD of DNGR-1 binds F-actin exposed by dead cell corpses and causes the receptor to signal and potentiate cross-presentation of dead cell-associated antigens by DCs. Here, we describe a conformational change that occurs in the neck region of DNGR-1 in a pH- and ionic strength-dependent manner and that controls cross-presentation of dead cell-associated antigens. We identify residues in the neck region that, when mutated, lock DNGR-1 in one of the two conformational states to potentiate cross-presentation. In contrast, we show that chimeric proteins in which the neck region of DNGR-1 is replaced by that of unrelated C-type lectin receptors fail to promote cross-presentation. Our results suggest that the neck region of DNGR-1 is an integral receptor component that senses receptor progression through the endocytic pathway and has evolved to maximize extraction of antigens from cell corpses, coupling DNGR-1 function to its cellular localization.

• Authors: Pavel Hanč, Oliver Schulz, Hanna Fischbach, Stephen R Martin, Svend Kjær, Caetano Reis e Sousa
• Journal: The EMBO journal (EMBO J) Vol. 35 Issue 22 Pg. 2484-2497 (11 15 2016) ISSN: 1460-2075 [Electronic] England
• PMID: 27753620 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

Chemical References

• Clec9a protein, mouse
• Lectins, C-Type
• Receptors, Immunologic

Topics

• Allosteric Regulation
• Animals
• DNA Mutational Analysis
• Dendritic Cells (metabolism)
• Hydrogen-Ion Concentration
• Lectins, C-Type (chemistry, genetics, metabolism)
• Mice
• Osmolar Concentration
• Protein Conformation (drug effects)
• Receptors, Immunologic (chemistry, genetics, metabolism)