Oligomerization domains in the glycan‐binding receptors DC‐SIGN and DC‐SIGNR: Sequence variation and stability differences

Abstract

Human dendritic cell‐specific intercellular adhesion molecule‐1 grabbing nonintegrin, DC‐SIGN, and the sinusoidal endothelial cell receptor DC‐SIGNR or L‐SIGN, are closely related sugar‐binding receptors. DC‐SIGN acts both as a pathogen‐binding endocytic receptor and as a cell adhesion molecule, while DC‐SIGNR has only the pathogen‐binding function. In addition to differences in the sugar‐binding properties of the carbohydrate‐recognition domains in the two receptors, there are sequence differences in the adjacent neck domains, which are coiled‐coil tetramerization domains comprised largely of 23‐amino acid repeat units. A series of model polypeptides consisting of uniform repeat units have been characterized by gel filtration, differential scanning calorimetry and circular dichroism. The results demonstrate that two features characterize repeat units which form more stable tetramers: a leucine reside in the first position of the heptad pattern of hydrophobic residues that pack on the inside of the coiled coil and an arginine residue on the surface of the coiled coil that forms a salt bridge with a glutamic acid residue in the same polypeptide chain. In DC‐SIGNR from all primates, very stable repeat units predominate, so the carbohydrate‐recognition domains must be held relatively closely together. In contrast, stable repeat units are found only near the membrane in DC‐SIGN. The presence of residues that disrupt tetramer formation in repeat units near the carbohydrate‐recognition domains of DC‐SIGN would allow these domains to splay further apart. Thus, the neck domains of DC‐SIGN and DC‐SIGNR can contribute to the different functions of these receptors by presenting the sugar‐binding sites in different contexts.

Efficient functional screening of a cellular cDNA library to identify severe fever with thrombocytopenia syndrome virus entry factors

“…has 7 tandem-repeats in the neck region [44][45][46] , and so did DC-SIGNR used in the characterisation of iVLP in this report (e.g. Fig.…”

“…The DC-SIGNR molecule has considerable polymorphism, especially within its neck region, which includes 3 to 9 highly conserved repeats containing 23 amino acids [44][45][46] and the polymorphism may affect host susceptibility to infection with some pathogens 46,50 . In the present study with a liver cDNA library, two variants of DC-SIGNR with 4 and 7 repeats in the neck regions were identified as SFTS virus entry factors, suggesting that polymorphism of DC-SIGNR may not be important in DC-SIGNR-mediated SFTS virus infection.…”

“…PCR with a pMX primer pair amplified an approximately 2 kb fragment from the Clone2 cellular genome (Fig. 4c) the sequence of which was determined to be a variant of DC-SIGNR, which had 4 tandem-repeats of 23 amino acids in the neck region 44,45 .…”

Dendritic cell biology and its role in tumor immunotherapy

“…It can also induce inflammasome activation in macrophages and stimulate the immune reaction of T cells [14]. The human DC-specific intercellular adhesion molecule-1 grabbing nonintegrin (DC-SIGN or CD209) is thought to be a canonical of the C-type lectin receptor expressed on both macrophages and DCs [15]. It is a type 2, mannose-specific C-type lectin that also works as a cytosolic DNA-sensor.…”

Mecanismos moleculares de reconhecimento das glicosilações do envelope do vírus da Dengue pelas lectinas tipo-C e seus potenciais inibidores

“…5a). Na superfície celular o receptor é encontrado como tetrâmeros estabilizados pelas repetições das hélices do pescoço67,68 , que formam uma estrutura do tipo haste rígida ligada de forma flexível aos CRDs69 . Uma consequência de tal flexibilidade entre os CRDs e o pescoço é que, conforme revelado por uma estrutura obtida por crio-microscopia eletrônica, apenas dois CRDs do receptor tetramérico interagem simultaneamente com as glicosilações do envelope viral70 .…”