embj.201694695.pdf (2.61 MB)
A pH- and ionic strength-dependent conformational change in the neck region regulates DNGR-1 function in dendritic cells
journal contributionposted on 2020-08-05, 16:52 authored by Pavel Hanč, Oliver Schulz, Hanna Fischbach, Stephen R Martin, Svend Kjær, Caetano Reis e Sousa
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.
C‐type lectin receptorscross‐presentationnecrosisprotein structureAllosteric RegulationAnimalsDNA Mutational AnalysisDendritic CellsHydrogen-Ion ConcentrationLectins, C-TypeMiceOsmolar ConcentrationProtein ConformationReceptors, ImmunologicReis e Sousa FC001136SBFC-ackGEP-ackDevelopmental Biology06 Biological Sciences08 Information and Computing Sciences11 Medical and Health Sciences