NMR studies of a viral protein that mimics the regulators of complement activation

Wiles, Alan P.; Shaw, Graeme L.; Bright, Jeremy R.; Perczel, András; Campbell, Iain D.; Barlow, Paul N.

doi:10.1006/jmbi.1997.1241

Cited by 120 publications

(124 citation statements)

References 63 publications

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“…Relative orientations of SCR1-3 are comparable to those in native VCP, with tilt, twist, and skew angles (ref. 42; native values in parentheses) of 65 (65), 2 (3), Ϫ78 (Ϫ76) and 62 (64), 30 (35), 110 (107), respectively, for one to two and two to three pairs; values for the SCR3-4 pair, 126 (99), 31 (3), Ϫ51 (Ϫ37), however, differ significantly, indicating substantial relative movement. Analysis using DYNDOM (38) shows that the motion is a 29.5°rotation of SCR4 about a hinge formed by residues 183 and 184, which are part of the linker (residues 183-187) between SCR3-4.…”

Section: Resultsmentioning

confidence: 99%

RETRACTED: Structure of vaccinia complement protein in complex with heparin and potential implications for complement regulation

Ganesh

Smith

Kotwal

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Vaccinia virus complement control protein (VCP), a homolog of the regulators of the complement activation family of proteins, inhibits complement activation through mechanisms similar to human fluid-phase complement regulators factor H and C4b-binding protein. VCP has a heparin-binding activity that assists vaccinia in host interactions. Interaction with cell-surface polyanions like heparin is centrally important in the functioning of fluid-phase complement regulators and is the basis of host-target discrimination by the alternative pathway. We report the structure of VCP in complex with a heparin decasaccharide, which reveals changes in VCP that might be pertinent to complement regulation. Properties that VCP shares with fluid-phase complement regulators suggest that such conformational changes may be of relevance in the functioning of other complement regulators. Additionally, comparison of VCP–heparin interactions with potentially similar interactions in factor H might enable understanding of the structural basis of familial hemolytic uremic syndrome, attributed to mutational disruption of heparin and C3b binding by factor H

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Section: Resultsmentioning

confidence: 99%

RETRACTED: Structure of vaccinia complement protein in complex with heparin and potential implications for complement regulation

Ganesh

Smith

Kotwal

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…This region was previously reported to consist of two juxtaposed gene modules belonging to the C4b-␤2 glycoprotein and EGF/LDL-receptor gene families (25,26). In light of more recent data, the C4b receptor-like domain was found to be a complement control protein repeat (CCP) which is present in the complement receptor type 1 (27), in the Vaccinia virus complement control protein (VCP) (28), and in the human Factor H (29,30). This short consensus repeat is formed by two disulfide bonds having features characteristic of a Sushi domain, i.e.…”

Section: Resultsmentioning

confidence: 99%

Molecular Model, Calcium Sensitivity, and Disease Specificity of a Conformational Thyroperoxidase B-cell Epitope

Estienne¹,

Blanchet²,

Niccoli-Sire³

et al. 1999

Journal of Biological Chemistry

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While studying the humoral mechanisms involved in thyroid autoimmunity, we located a B-cell autoepitope in the extracellular C-terminal region of human thyroperoxidase. Structural modeling showed that this region encompasses both a Sushi-like and an epidermal growth factor-like domain, the flexible arrangement of which was putatively stabilized by calcium. The recombinant peptide was found to contain the previously identified conformational thyroperoxidase autoepitope. The occurrence of a calcium-induced conformational change was confirmed using a recombinant peptide monoclonal antibody, the decrease of which in binding to calcium-saturated thyroperoxidase was reversed by a chelating agent. The disease specificity of recombinant peptide, which was more frequently recognized by Hashimoto's than by Graves' patients, adds to its potential value as a diagnostic and preventive tool in the context of B-cell autoimmunity. Thyroperoxidase (TPO)1 plays a key role in the biosynthesis of thyroid hormones by catalyzing both the iodination of tyrosine residues and the coupling of some iodotyrosine residues in thyroglobulin to form tri-and tetraiodothyronines. It is a hemecontaining membrane enzyme which is expressed at the apical pole of thyrocytes facing the colloid space (1). TPO belongs to the mammalian peroxidase family, the members of which include myelo-, lacto-, eosinophil, and salivary peroxidases (2). Human TPO contains 933 amino acids (aa), and shows a large extracellular region consisting of 848 aa and five potential glycosylation sites, a short membrane-spanning region, and a 61-aa cytoplasmic tail. Most of the extracellular region of TPO shows a high degree of homology with myeloperoxidase (aa 1-739). The extracellular region close to the membrane anchorage domain shows homologies with the C4b complement component (aa 739 -794) and EGF (aa 794 -842) (3). The threedimensional structure of TPO is not yet known, and elucidating this point constitutes an important task for scientists investigating the peroxidase family and for immunologists focusing on autoimmunity questions because TPO is a major thyroid autoantigen.Autoantibodies (aAb) to TPO are the most sensitive and specific serological markers available for diagnosing autoimmune thyroid diseases. Like most antibodies to exogenous antigens, TPO aAb are produced by B lymphocytes via a T-celldependent mechanism involving specific cellular receptors and soluble cytokines. At the molecular level, however, the specificity of the autoimmune reaction relies on the recognition of TPO epitopes by T and B-cells (4). T-cell receptors recognize linear epitopes from processed TPO associated with class II molecules belonging to the major histocompatibility complex, which are co-expressed at the surface of antigen-presenting cells. By contrast, B-cell receptors, which are membrane-bound immunoglobulins, usually have a more stringent specificity and recognize conformational epitopes, i.e. they are highly dependent on the three-dimensional structure of the TPO molecule (5-7).

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“…Although it could be argued that the poorly structured nature of CCP1 is an artifact of expression, the compact folding of CCP2 and the successful expression in P. pastoris of many other CCP modules suggest otherwise (50,58,(62)(63)(64). Furthermore, when the two modules are expressed together, the second (but not the first) module is compactly folded, and there is only a small degree of stabilization imparted to CCP1 by CCP2 despite the potential for a relatively extensive intermodular junction involving the hypervariable loop of CCP2.…”

Section: Discussionmentioning

confidence: 99%

Structural Analysis of the Complement Control Protein (CCP) Modules of GABAB Receptor 1a

Blein

Ginham

Uhrı́n

et al. 2004

Journal of Biological Chemistry

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The ␥-aminobutyric acid type B (GABA B ) receptor is a heterodimeric G-protein-coupled receptor. In humans, three splice variants of the GABA B receptor 1 (R1) subunit differ in having one, both, or neither of two putative complement control protein (CCP) modules at the extracellular N terminus, prior to the GABA-binding domain. The in vivo function of these predicted modules remains to be discovered, but a likely association with extracellular matrix proteins is intriguing. The portion of the GABA B R1a variant encompassing both of its CCP module-like sequences has been expressed, as have the sequences corresponding to each individual module. Each putative CCP module exhibits the expected pattern of disulfide formation. However, the second module (CCP2) is more compactly folded than the first, and the three-dimensional structure of this more C-terminal module (expressed alone) was solved on the basis of NMRderived nuclear Overhauser effects. This revealed a strong similarity to previously determined CCP module structures in the regulators of complement activation. The N-terminal module (CCP1) displayed conformational heterogeneity under a wide range of conditions whether expressed alone or together with CCP2. Several lines of evidence indicated the presence of native disorder in CCP1, despite the fact that recombinant CCP1 contributes to binding to the extracellular matrix protein fibulin-2. Thus, we have shown that the two CCP modules of GABA B R1a have strikingly different structural properties, reflecting their different functions.␥-Aminobutyric acid (GABA) 1 is the principal inhibitory neurotransmitter of the vertebrate central nervous system. It is the ligand for both ionotropic GABA type A receptors and metabotropic GABA type B (GABA B ) receptors. GABA B receptors belong to G-protein-coupled receptor class III, which includes metabotropic glutamate receptors, Ca 2ϩ -sensing receptors, and some pheromone and taste receptors (1). Agonist and antagonists of GABA B receptors have been shown to be effective in clinical cases or animal models of nociception, depression, addiction, epilepsy, and cognitive impairment. Selective GABA B receptor ligands could also be useful in the treatment of peripheral nervous system disorders (2, 3).The GABA B receptor is composed of subunits termed GABA B R1 and GABA B R2, both of which are needed for receptor function (4 -7). The two subunits share a similar molecular architecture, common to all class III G-protein-coupled receptors, consisting of a large extracellular N-terminal domain encompassing a ligand-binding site, followed by a transmembrane heptahelical domain and an intracellular C-terminal tail. Coupling to G-proteins is mediated by the intracellular loops connecting the transmembrane helices and the C-terminal region.In class III G-protein-coupled receptors, the extracellular domain of each subunit is proposed to have a dynamic bilobate structure, where the two globular lobes form a "clamshell"-like shape. The current model for the function of these dimers suggest...

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NMR studies of a viral protein that mimics the regulators of complement activation

Cited by 120 publications

References 63 publications

RETRACTED: Structure of vaccinia complement protein in complex with heparin and potential implications for complement regulation

RETRACTED: Structure of vaccinia complement protein in complex with heparin and potential implications for complement regulation

Molecular Model, Calcium Sensitivity, and Disease Specificity of a Conformational Thyroperoxidase B-cell Epitope

Structural Analysis of the Complement Control Protein (CCP) Modules of GABAB Receptor 1a

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