Crystal Structure of Trimeric Carbohydrate Recognition and Neck Domains of Surfactant Protein A

Head, James F.; Mealy, Tanya R.; McCormack, Francis X.; Seaton, Barbara A.

doi:10.1074/jbc.m305628200

Cited by 101 publications

(144 citation statements)

References 53 publications

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“…This arrangement contrasts with the close and fixed association of the CRD with trimeric ␣-helical neck regions in the collectins (23)(24)(25), and it suggests that the CRDs and the necks may be independently folded units in DC-SIGN and DC-SIGNR. To test this hypothesis, differential scanning calorimetry was performed on the CRD alone and the extracellular domain fragment containing seven repeats.…”

Section: Table III Variable Orientations Of Crds With Respect To the mentioning

confidence: 73%

Extended Neck Regions Stabilize Tetramers of the Receptors DC-SIGN and DC-SIGNR

Feinberg

Guo

Mitchell

et al. 2005

Journal of Biological Chemistry

173

218

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The human cell surface receptors DC-SIGN (dendritic cell-specific intercellular adhesion molecule-grabbing nonintegrin) and DC-SIGNR (DC-SIGN-related) bind to oligosaccharide ligands found on human tissues as well as on pathogens including viruses, bacteria, and parasites. The extracellular portion of each receptor contains a membrane-distal carbohydrate-recognition domain (CRD) and forms tetramers stabilized by an extended neck region consisting of 23 amino acid repeats. Cross-linking analysis of full-length receptors expressed in fibroblasts confirms the tetrameric state of the intact receptors. Hydrodynamic studies on truncated receptors demonstrate that the portion of the neck of each protein adjacent to the CRD is sufficient to mediate the formation of dimers, whereas regions near the N terminus are needed to stabilize the tetramers. Some of the intervening repeats are missing from polymorphic forms of DC-SIGNR. Two different crystal forms of truncated DC-SIGNR comprising two neck repeats and the CRD reveal that the CRDs are flexibly linked to the neck, which contains ␣-helical segments interspersed with non-helical regions. Differential scanning calorimetry measurements indicate that the neck and CRDs are independently folded domains. Based on the crystal structures and hydrodynamic data, models for the full extracellular domains of the receptors have been generated. The observed flexibility of the CRDs in the tetramer, combined with previous data on the specificity of these receptors, suggests an important role for oligomerization in the recognition of endogenous glycans, in particular those present on the surfaces of enveloped viruses recognized by these proteins.The dendritic cell receptor DC-SIGN 1 and the closely related DC-SIGNR found on endothelial cells have been of considerable interest because of their ability to enhance infection of T cells by the human immunodeficiency virus and because of their interactions with glycoproteins found on the surface of other enveloped viruses (1, 2). The physiological functions of these receptors are not known with certainty, but DC-SIGN has been ascribed roles in binding to intercellular adhesion molecule 3 on T cells and intercellular adhesion molecule 2 on endothelia, as well as in uptake of pathogens (3-7). Although DC-SIGN binds to a broad spectrum of glycans, it has highest affinity for N-linked high mannose oligosaccharides and fucose-containing structures that are found both as blood group antigens in human tissues and on the surfaces of certain parasites (7,8). DC-SIGNR binds only to the high mannose oligosaccharides, and unlike DC-SIGN, it does not mediate uptake and degradation of glycoconjugates (8).DC-SIGN and DC-SIGNR share nearly 80% sequence identity and are closely similar in overall architecture. Both receptors are type II transmembrane proteins in which C-terminal C-type carbohydrate-recognition domains (CRDs) are projected from the cell surface by a neck comprising a series of highly conserved 23-amino acid repeats. There are seven complete re...

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Section: Table III Variable Orientations Of Crds With Respect To the mentioning

confidence: 73%

Extended Neck Regions Stabilize Tetramers of the Receptors DC-SIGN and DC-SIGNR

Feinberg

Guo

Mitchell

et al. 2005

Journal of Biological Chemistry

173

218

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“…The trimeric crystal structure of neither the human SP-A nor the baboon SP-A is available in the Protein Data Bank (PDB; http://www.rcsb.org/pdb) (Berman et al, 2000). Head et al (2003) solved the crystal structure of the trimeric carbohydrate recognition domain/neck domain of SP-A. However, the PDB file and X-ray structure in the PDB were available for the monomeric subunit of rat SP-A (PDB ID 1R13) (Head et al, 2003).…”

Section: Protein-protein Docking and Prediction Of Interacting Amino mentioning

confidence: 99%

“…Head et al (2003) solved the crystal structure of the trimeric carbohydrate recognition domain/neck domain of SP-A. However, the PDB file and X-ray structure in the PDB were available for the monomeric subunit of rat SP-A (PDB ID 1R13) (Head et al, 2003). Using bioinformatics approaches, it is possible to obtain the structure of trimer by docking three monomers to form a single complex.…”

Section: Protein-protein Docking and Prediction Of Interacting Amino mentioning

confidence: 99%

A Toll-Like Receptor-4-Interacting Surfactant Protein-A-Derived Peptide Suppresses Tumor Necrosis Factor-α Release from Mouse JAWS II Dendritic Cells

Awasthi¹,

Brown²,

King³

et al. 2010

J Pharmacol Exp Ther

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Surfactant protein-A (SP-A) and Toll-like receptor-4 (TLR4) proteins are recognized as pathogen-recognition receptors. An exaggerated activation of TLR4 induces inflammatory response, whereas SP-A protein down-regulates inflammation. We hypothesized that SP-A-TLR4 interaction may lead to inhibition of inflammation. In this study, we investigated interaction between native baboon lung SP-A and baboon and human TLR4-MD2 proteins by coimmunoprecipitation/immunoblotting and microwell-based methods. The interaction between SP-A and TLR4-MD2 proteins was then analyzed using a bioinformatics approach. In the in silico model of SP-A-TLR4 -MD2 complex, we identified potential binding regions and amino acids at the interface of SP-A-TLR4. Using this information, we synthesized a library of human SP-A-derived peptides that contained interacting amino acids. Next, we tested whether the TLR4-interacting SP-A peptides would suppress inflammatory cytokines. The peptides were screened for any changes in the tumor necrosis factor-␣ (TNF-␣) response against lipopolysaccharide (LPS) stimuli in the mouse JAWS II dendritic cell line. Different approaches used in this study suggested binding between SP-A and TLR4-MD2 proteins. In cells pretreated with peptides, three of seven peptides increased TNF-␣ production against LPS. However, two of these peptides (SPA4: GDFRYSDGTPVNYTNWYRGE and SPA5: YVGLTEGPSPGDFRYSDFTP) decreased the TNF-␣ production in LPS-challenged JAWS II dendritic cells; SPA4 peptide showed more pronounced inhibitory effect than SPA5 peptide. In conclusion, we identify a human SP-A-derived peptide (SPA4 peptide) that interacts with TLR4-MD2 protein and inhibits the LPS-stimulated release of TNF-␣ in JAWS II dendritic cells.

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“…Although the X-ray crystallographic structure for CRP and the way it binds phosphorylcholine are known, the manner in which this protein binds (oxidized) PC and PAF is not known (48). The X-ray crystallographic structure for SP-A has recently been solved (14), and a putative binding site for the polar phosphorylcholine moiety of DPPC has been identified within the carbohydrate recognition domain. Furthermore, the exposed face of the carbohydrate recognition domain contains an elongated hydrophobic region that would likely account for the ability of the collectin to bind DPPC.…”

Section: Discussionmentioning

confidence: 99%

Disparate effects of two phosphatidylcholine binding proteins, C-reactive protein and surfactant protein A, on pulmonary surfactant structure and function

Nag¹,

Rodríguez-Capote²,

Panda³

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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C-reactive protein (CRP) and surfactant protein A (SP-A) are phosphatidylcholine (PC) binding proteins that function in the innate host defense system. We examined the effects of CRP and SP-A on the surface activity of bovine lipid extract surfactant (BLES), a clinically applied modified natural surfactant. CRP inhibited BLES adsorption to form a surface-active film and the film's ability to lower surface tension (γ) to low values near 0 mN/m during surface area reduction. The inhibitory effects of CRP were reversed by phosphorylcholine, a water-soluble CRP ligand. SP-A enhanced BLES adsorption and its ability to lower γ to low values. Small amounts of SP-A blocked the inhibitory effects of CRP. Electron microscopy showed CRP has little effect on the lipid structure of BLES. SP-A altered BLES multilamellar vesicular structure by generating large, loose bilayer structures that were separated by a fuzzy amorphous material, likely SP-A. These studies indicate that although SP-A and CRP both bind PC, there is a difference in the manner in which they interact with surface films.

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Crystal Structure of Trimeric Carbohydrate Recognition and Neck Domains of Surfactant Protein A

Abstract: Surfactant protein A (SP-A

Cited by 101 publications

References 53 publications

Extended Neck Regions Stabilize Tetramers of the Receptors DC-SIGN and DC-SIGNR

Extended Neck Regions Stabilize Tetramers of the Receptors DC-SIGN and DC-SIGNR

A Toll-Like Receptor-4-Interacting Surfactant Protein-A-Derived Peptide Suppresses Tumor Necrosis Factor-α Release from Mouse JAWS II Dendritic Cells

Disparate effects of two phosphatidylcholine binding proteins, C-reactive protein and surfactant protein A, on pulmonary surfactant structure and function

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