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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.

SUBMITTER: Hanc P

PROVIDER: S-EPMC5109244 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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

Hanč Pavel P Schulz Oliver O Fischbach Hanna H Martin Stephen R SR Kjær Svend S Reis e Sousa Caetano C

The EMBO journal 20161017 22

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 regio ...[more]

PMID: 27753620

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Project description:The Dengue has become a global public health threat, with over 100 million infections annually; to date there is no specific vaccine or any antiviral drug. The structures of the envelope (E) proteins of the four known serotype of the dengue virus (DENV) are already known, but there are insufficient molecular details of their structural behavior in solution in the distinct environmental conditions in which the DENVs are submitted, from the digestive tract of the mosquito up to its replication inside the host cell. Such detailed knowledge becomes important because of the multifunctional character of the E protein: it mediates the early events in cell entry, via receptor endocytosis and, as a class II protein, participates determinately in the process of membrane fusion. The proposed infection mechanism asserts that once in the endosome, at low pH, the E homodimers dissociate and insert into the endosomal lipid membrane, after an extensive conformational change, mainly on the relative arrangement of its three domains. In this work we employ all-atom explicit solvent Molecular Dynamics simulations to specify the thermodynamic conditions in that the E proteins are induced to experience extensive structural changes, such as during the process of reducing pH. We study the structural behavior of the E protein monomer at acid pH solution of distinct ionic strength. Extensive simulations are carried out with all the histidine residues in its full protonated form at four distinct ionic strengths. The results are analyzed in detail from structural and energetic perspectives, and the virtual protein movements are described by means of the principal component analyses. As the main result, we found that at acid pH and physiological ionic strength, the E protein suffers a major structural change; for lower or higher ionic strengths, the crystal structure is essentially maintained along of all extensive simulations. On the other hand, at basic pH, when all histidine residues are in the unprotonated form, the protein structure is very stable for ionic strengths ranging from 0 to 225 mM. Therefore, our findings support the hypothesis that the histidines constitute the hot points that induce configurational changes of E protein in acid pH, and give extra motivation to the development of new ideas for antivirus compound design.

Dataset Information

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

Publications

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

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