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Geometry and adhesion of extracellular domains of DC-SIGNR neck length variants analyzed by force-distance measurements.

Leckband DE, Menon S, Rosenberg K, Graham SA, Taylor ME, Drickamer K - Biochemistry (2011)

Bottom Line: The results also validate a model for the extracellular domain of DC-SIGNR derived from crystallographic studies.Force measurements were performed with DC-SIGNR variants that differ in the length of the neck that result from genetic polymorphisms, which encode different numbers of the 23-amino acid repeat sequences that constitute the neck.In addition, differences in the lengths of DC-SIGN and DC-SIGNR extracellular domains with equivalent numbers of neck repeats support a model in which the different dispositions of the carbohydrate-recognition domains in DC-SIGN and DC-SIGNR result from variations in the sequences of the necks.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.

ABSTRACT
Force-distance measurements have been used to examine differences in the interaction of the dendritic cell glycan-binding receptor DC-SIGN and the closely related endothelial cell receptor DC-SIGNR (L-SIGN) with membranes bearing glycan ligands. The results demonstrate that upon binding to membrane-anchored ligand, DC-SIGNR undergoes a conformational change similar to that previously observed for DC-SIGN. The results also validate a model for the extracellular domain of DC-SIGNR derived from crystallographic studies. Force measurements were performed with DC-SIGNR variants that differ in the length of the neck that result from genetic polymorphisms, which encode different numbers of the 23-amino acid repeat sequences that constitute the neck. The findings are consistent with an elongated, relatively rigid structure of the neck repeat observed in crystals. In addition, differences in the lengths of DC-SIGN and DC-SIGNR extracellular domains with equivalent numbers of neck repeats support a model in which the different dispositions of the carbohydrate-recognition domains in DC-SIGN and DC-SIGNR result from variations in the sequences of the necks.

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Organization of the extracellular domain of DC-SIGNR. (A) Length variants of DC-SIGNR (left) and corresponding truncated, His6-tagged proteins used for force–distance measurements (right). (B) Comparison of proposed organization of DC-SIGN and DC-SIGNR based on crystal structures of DC-SIGNR fragments.(17) (C) Configuration of DC-SIGNR and neoglycolipid in force measurements. D is the absolute separation between the bilayer surfaces.
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fig1: Organization of the extracellular domain of DC-SIGNR. (A) Length variants of DC-SIGNR (left) and corresponding truncated, His6-tagged proteins used for force–distance measurements (right). (B) Comparison of proposed organization of DC-SIGN and DC-SIGNR based on crystal structures of DC-SIGNR fragments.(17) (C) Configuration of DC-SIGNR and neoglycolipid in force measurements. D is the absolute separation between the bilayer surfaces.

Mentions: In addition to these differences in the ligand-binding domains of DC-SIGN and DC-SIGNR, there appear to be significant but less well understood differences in their overall architectures (Figure 1A,B). In both receptors, the carbohydrate-recognition domains are projected from the cell surface by a neck domain comprising multiple copies of a 23-amino acid repeat sequence, but the number of copies of the repeat is largely fixed fixed at 7.5 in DC-SIGN, while polymorphisms in the gene for DC-SIGNR result in variant forms of the neck containing between 4.5 and 9.5 repeats.12,13 The allele frequency of the 7.5-repeat variant is over 50% in the human population, but the frequencies of the 6.5- and 5.5-repeat variants are 12–16% and 26–37%, respectively. Different neck-length genotypes have been associated with variations in susceptibility to certain viral infections. The 7.5-repeat form is more common in HIV-infected individuals than in uninfected individuals.(14) However, this correlation with HIV susceptibility has not been observed in all cases.(12) The presence of 4.5-repeat and 9.5-repeat variants correlates with decreased viral load in hepatitis C virus infection.(15) The shorter necks are also associated with diminished rates of SARS coronavirus infection.(16)


Geometry and adhesion of extracellular domains of DC-SIGNR neck length variants analyzed by force-distance measurements.

Leckband DE, Menon S, Rosenberg K, Graham SA, Taylor ME, Drickamer K - Biochemistry (2011)

Organization of the extracellular domain of DC-SIGNR. (A) Length variants of DC-SIGNR (left) and corresponding truncated, His6-tagged proteins used for force–distance measurements (right). (B) Comparison of proposed organization of DC-SIGN and DC-SIGNR based on crystal structures of DC-SIGNR fragments.(17) (C) Configuration of DC-SIGNR and neoglycolipid in force measurements. D is the absolute separation between the bilayer surfaces.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3140775&req=5

fig1: Organization of the extracellular domain of DC-SIGNR. (A) Length variants of DC-SIGNR (left) and corresponding truncated, His6-tagged proteins used for force–distance measurements (right). (B) Comparison of proposed organization of DC-SIGN and DC-SIGNR based on crystal structures of DC-SIGNR fragments.(17) (C) Configuration of DC-SIGNR and neoglycolipid in force measurements. D is the absolute separation between the bilayer surfaces.
Mentions: In addition to these differences in the ligand-binding domains of DC-SIGN and DC-SIGNR, there appear to be significant but less well understood differences in their overall architectures (Figure 1A,B). In both receptors, the carbohydrate-recognition domains are projected from the cell surface by a neck domain comprising multiple copies of a 23-amino acid repeat sequence, but the number of copies of the repeat is largely fixed fixed at 7.5 in DC-SIGN, while polymorphisms in the gene for DC-SIGNR result in variant forms of the neck containing between 4.5 and 9.5 repeats.12,13 The allele frequency of the 7.5-repeat variant is over 50% in the human population, but the frequencies of the 6.5- and 5.5-repeat variants are 12–16% and 26–37%, respectively. Different neck-length genotypes have been associated with variations in susceptibility to certain viral infections. The 7.5-repeat form is more common in HIV-infected individuals than in uninfected individuals.(14) However, this correlation with HIV susceptibility has not been observed in all cases.(12) The presence of 4.5-repeat and 9.5-repeat variants correlates with decreased viral load in hepatitis C virus infection.(15) The shorter necks are also associated with diminished rates of SARS coronavirus infection.(16)

Bottom Line: The results also validate a model for the extracellular domain of DC-SIGNR derived from crystallographic studies.Force measurements were performed with DC-SIGNR variants that differ in the length of the neck that result from genetic polymorphisms, which encode different numbers of the 23-amino acid repeat sequences that constitute the neck.In addition, differences in the lengths of DC-SIGN and DC-SIGNR extracellular domains with equivalent numbers of neck repeats support a model in which the different dispositions of the carbohydrate-recognition domains in DC-SIGN and DC-SIGNR result from variations in the sequences of the necks.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.

ABSTRACT
Force-distance measurements have been used to examine differences in the interaction of the dendritic cell glycan-binding receptor DC-SIGN and the closely related endothelial cell receptor DC-SIGNR (L-SIGN) with membranes bearing glycan ligands. The results demonstrate that upon binding to membrane-anchored ligand, DC-SIGNR undergoes a conformational change similar to that previously observed for DC-SIGN. The results also validate a model for the extracellular domain of DC-SIGNR derived from crystallographic studies. Force measurements were performed with DC-SIGNR variants that differ in the length of the neck that result from genetic polymorphisms, which encode different numbers of the 23-amino acid repeat sequences that constitute the neck. The findings are consistent with an elongated, relatively rigid structure of the neck repeat observed in crystals. In addition, differences in the lengths of DC-SIGN and DC-SIGNR extracellular domains with equivalent numbers of neck repeats support a model in which the different dispositions of the carbohydrate-recognition domains in DC-SIGN and DC-SIGNR result from variations in the sequences of the necks.

Show MeSH
Related in: MedlinePlus