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PubMed2002

[The study of correlation between HPV and vocal cord polyp].

OBJECTIVE: To reveal the correlation between HPV and human vocal cord polyp (vcp). METHOD: Analyzed the morphological changes of 99 vocal cord polyps stained with HE by microscope and 11 specimen by transmission electron microscopy and scanning electron microscopy; Meanwhile, HPV-DNA were detected in 50 vcp by PCR, and then a comparison analysis with the pathological results of vcp was made. RESULT: Koilocytoid cells were observed in 55 of 99 vcp (55.6%); The presence of HPV-DNA were detected in 34 of 50 vcp (68%), HPV-DNA positive rate was 92.9% and 36.4% respectively in 34 cases with koilocyte-like cells expression and 22 cases without koilcyte-like cells expression; there was significant different. The results of electron microscopy agreed with the results under light microscopy except koilocyte-like cell expression. CONCLUSION: There is obvious correlation between HPV and vcp, HPV may play certain role in the occurrence of vcp.

Adolescent↗

PubMed1998

Interaction of vaccinia virus complement control protein with human complement proteins: factor I-mediated degradation of C3b to iC3b1 inactivates the alternative complement pathway.

Vaccinia virus complement control protein (VCP) is a virulence determinant of vaccinia virus that helps protect the virus from the complement attack of the host. To characterize the interaction of VCP with C3 and C4 and understand the mechanism by which VCP inactivates complement, we have expressed VCP in a yeast expression system and compared the biologic activity of the purified protein to that of human factor H and complement receptor 1 (CR1). Recombinant VCP bound to C3 and the proteolytically cleaved form of C3 (C3b), but not to the 135,300-m.w. fragment of C3 generated using elastase (C3c) and the 35,000-m.w. fragment of C3 generated using elastase (C3d) and inhibited both the classical and alternative pathways of complement activation. Although rVCP was less effective at inhibiting the alternative pathway than factor H or CR1, it was more effective than factor H at inhibiting the classical pathway. Unlike factor H, rVCP was unable discriminate between alternative pathway-mediated lysis of rabbit and sheep E. A comparison of the cofactor activity in factor I-mediated cleavage of C3b suggested that in contrast to factor H and CR1, which displayed cofactor activity for the three sites, rVCP displayed cofactor activity primarily for the first site, leading to generation of C3b cleaved by factor I between Arg1281-Ser1282 (iC3b1). Its cofactor activity for C4b cleavages was similar to that of soluble complement receptor type 1. Purification and functional analysis of iC3b1 showed that it was unable to interact with factor B to form the alternative pathway C3 convertase, C3b,Bb. These results suggest that the interaction of VCP with C3 is different from that of factor H and CR1 and that VCP-supported first cleavage of C3b by factor I is sufficient to render C3b nonfunctional.

Arginine↗

PubMed1999

[Hemodynamic effects of a ventriculo-cisternal perfusion of bupivacaine].

OBJECTIVES: The cardiotoxic properties of bupivacain have been well documented under in-vitro, as well as under in-vivo conditions. A further mechanism of cardiovascular impairment by bupivacaine via the central nervous system gained investigational interest in animal studies. The aim of our study was to demonstrate the effect of a ventriculocisternal perfusion of bupivacain on systemic hemodynamic variables and their reversibility by wash-out with mock-CSF. METHODS: After obtaining animal investional committee consent, nine anaesthetized and relaxed pigs were prepared for a ventriculocisternal perfusion (VCP). Hemodynamic data were obtained by invasive blood pressure measurements in the high and low pressure system as well as cardiac output (thermodilution technique), intracranial pressure and electrocardiogram. Systemic vascular resistance and stroke volume were calculated using standard formulas. A second group of three animals were exposed to an intravenous infusion of the same dose of bupivacain over the same period of time to rule out direct cardiac effects. After instrumentation baseline data were obtained (K0 1) under VCP with mock-CSF for 30 minutes. The mock-CSF was replaced by 0.05% bupivacaine in mock-CSF and VCP was continued with 3 ml.h-1 for 20 minutes. After administration of 500 micrograms bupivacaine data were collected (BU). The bupivacaine solution was replaced by mock-CSF and after twenty minutes hemodynamic measurement were repeated (K02). RESULTS: The intravenous administration of 500 micrograms bupivacaine had no effect on all measured variables. VCP of the same dose resulted in significant increase in heart rate, systolic, diastolic and mean arterial blood pressures. Left and right heart filling pressures as well as systemic vascular resistance were not affected while the stroke volume decreased. After continuation of VCP with mock-CSF hemodynamic changes were reversed. DISCUSSION: Our results demonstrate that bupivacaine initiates an indirect cardiovascular stimulating effect of a VCP with 500 micrograms of bupivacaine via the central nervous system. The intravenous administration of the same dose had no effect. The centrally mediated cardiovascular effect of bupivacaine was reversed by wash-out with mock-CSF. The cardiovascular stimulation observed in this animal experiment may be of clinical relevance as a potential sign of toxic effects of bupivacaine on the CNS.

Anesthetics, Local↗

PubMed2006

Forearm cephalic vein cross-sectional area changes at incremental congestion pressures: towards a standardized and reproducible vein mapping protocol.

OBJECTIVES: Duplex ultrasonography assessment of superficial forearm veins is frequently used before a hemodialysis arteriovenous fistula (AVF) is created. There is, however, no standardized preoperative duplex ultrasonography protocol. This study assessed B-mode image analysis reproducibility and reproducibility of repeated forearm superficial venous diameter measurements on different days at different venous congestion pressures (VCPs). METHODS: Diameters were determined using B-mode ultrasonography in 10 healthy male volunteers on days 1 and 14 at incremental VCP values (10 to 80 mm Hg). Intra- and interobserver agreement was assessed for B-mode image analysis by calculating interclass correlation coefficients (ICC). Reproducibility of repeated diameter measurements (maximum and minimum diameter at days 1 and 14), cross-sectional area size increase, and shape change due to incremental VCPs were determined by calculating ICC values. RESULTS: Analysis of intraobserver agreement of B-mode image interpretation yielded ICC values of 0.97 (95% confidence interval [CI], 0.94 to 0.99) and 0.97 (95% CI, 0.96 to 0.99) for determination of maximum and minimum diameters, respectively. Interobserver agreement analysis yielded ICC values of 0.95 (95% CI, 0.92 to 0.97) and 0.96 (95% CI, 0.96 to 0.99) for determination of maximum and minimum diameters, respectively. Reproducibility of repeated diameter measurements on days 1 and 14 improved substantially at incremental VCP values, with best reproducibility at VCPs >40 mm Hg. Repeated determination of cross-sectional area size increase and shape change due to VCP increase from 10 to 80 mm Hg yielded ICC values of 0.49 (95% CI, 0.19 to 1.00) and 0.09 (95% CI, 0.00 to 0.92), respectively. Maximum and minimum diameters as well as cross-sectional area size increased significantly (P < .01) due to VCP increase during both sessions. Cross-sectional area shape changed significantly (P < .01) due to VCP increase during both sessions. CONCLUSIONS: Diameter measurements on B-mode images are largely observer independent. Superficial venous cross-sectional area shape is noncircular, and cross-sectional area size depends on VCP. Both maximum and minimum venous diameters should be determined at VCPs >40 mm Hg to attain the best reproducibility. Further studies are needed to determine whether a standardized preoperative vein mapping protocol can reduce AVF nonmaturation rates.

Adult↗

PubMed2000

Specificity of Ca2+-dependent protein interactions mediated by the C2A domains of synaptotagmins.

Synaptotagmins represent a family of neuronal proteins thought to function in membrane traffic. The best characterized synaptotagmin, synaptotagmin I, is essential for fast Ca2+-dependent synaptic vesicle exocytosis, indicating a role in the Ca2+ triggering of membrane fusion. Synaptotagmins contain two C2 domains, the C2A and C2B domains, which bind Ca2+ and may mediate their functions by binding to specific targets. For synaptotagmin I, several putative targets have been identified, including the SNARE proteins syntaxin and SNAP-25. However, it is unclear which of the many binding proteins are physiologically relevant. Furthermore, more than 10 highly homologous synaptotagmins are expressed in brain, but it is unknown if they execute similar binding reactions. To address these questions, we have performed a systematic, unbiased study of proteins which bind to the C2A domains of synaptotagmins I-VII. Although the various C2A domains exhibit similar binding activities for phospholipids and syntaxin, we found that they differ greatly in their protein binding patterns. Surprisingly, none of the previously characterized binding proteins for synaptotagmin I are among the major interacting proteins identified. Instead, several proteins that were not known to interact with synaptotagmin I were bound tightly and stoichiometrically, most prominently the NSF homologue VCP, which is thought to be involved in membrane fusion, and an unknown protein of 40 kDa. Point mutations in the Ca2+ binding loops of the C2A domain revealed that the interactions of these proteins with synaptotagmin I were highly specific. Furthermore, a synaptotagmin I/VCP complex could be immunoprecipitated from brain homogenates in a Ca2+-dependent manner, and GST-VCP fusion proteins efficiently captured synaptotagmin I from brain. However, when we investigated the tissue distribution of VCP, we found that, different from synaptic proteins, VCP was not enriched in brain and exhibited no developmental increase paralleling synaptogenesis. Moreover, binding of VCP, which is an ATPase, to synaptotagmin I was inhibited by both ATP and ADP, indicating that the native, nucleotide-occupied state of VCP does not bind to synaptotagmin. Together our findings suggest that the C2A-domains of different synaptotagmins, despite their homology, exhibit a high degree of specificity in their protein interactions. This is direct evidence for diverse roles of the various synaptotagmins in brain, consistent with their differential subcellular localizations. Furthermore, our results indicate that traditional approaches, such as affinity chromatography and immunoprecipitations, are useful tools to evaluate the overall spectrum of binding activity for a protein but are not sufficient to estimate physiological relevance.

Adenosine Diphosphate↗

PubMed1999

Effect of prolonged restriction of motor activity on primates hydration homeostasis.

It has been assumed that restriction of motor activity (hypokinesia) induces significant changes in body hydration homeostasis. Thus, the objective of this study was to measure body hydration level during prolonged hypokinesia (HK). The studies were done on 12 male Macaca Mulatta (rhesus monkeys) aged three to five years (4.75 to 6.96 kg) during a 15-day period of pre HK and a 90-day period of HK. All primates were divided equally into two groups: monkeys placed under vivarium conditions served as vivarium control primates (VCP) and monkeys subjected to HK served as hypokinetic primates (HKP). For simulation of the HK effect, the HKM group was kept for 90 days in small individual cages that restricted their movements in all directions without hindering food and water intakes. During the pre HK period of 15 days and the HK period of 90 days the following parameters were measured: total body water (TBW), extracellular fluid volume (EFV), intracellular fluid volume (IFV), circulating plasma volume (CPV) and interstitial fluid volume (IsFV), urinary and plasma sodium and potassium, fluid consumption and elimination in urine, and body weight. Significant (p < or = 0.01) decrease in the TBW, IFV, and CPV was observed in the HKP group when compared with the VCP group. In the HKP group EFV and IsFV decreased significantly (p < or = 0.01) when compared with the VCP group only in the initial seven days of the HK period, while after the 7th day progressive increase could be observed. Fluid loss, urinary electrolyte excretion and plasma electrolyte concentration increased significantly (p < or = 0.01), while fluid intakes decreased significantly (p < or = 0.01) in the HKP group when compared with the VCP group. In the HKP group body weight decreased significantly (p < or = 0.01) when compared with the VCP group. In the VCP group the measured parameters did not change significantly when compared with the baseline control values. It was concluded that prolonged exposure to HK induces significant changes in body hydration homeostasis while body dehydration in monkeys caused primarily due to decreased CPV.

Animals↗

PubMed2004

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

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.

Amino Acid Sequence↗

PubMed1991

An extraovarian protein accumulated in mosquito oocytes is a carboxypeptidase activated in embryos.

We report a phenomenon previously unknown for oviparous animals; in Aedes aegypti mosquitoes a serine carboxypeptidase is synthesized extraovarially and then internalized by oocytes. The cDNA encoding mosquito vitellogenic carboxypeptidase (VCP) was cloned and sequenced. The VCP cDNA hybridizes to a 1.5-kilobase mRNA present only in the fat body of vitellogenic females. The deduced amino acid sequence of VCP shares significant homology with members of the serine carboxypeptidase family. Binding assays using a serine protease inhibitor, [3H]diisopropyl fluorophosphate, showed that VCP is activated in eggs at the onset of embryonic development. Activation of VCP is associated with the reduction in its size from 53 kDa (inactive proenzyme) to 48 kDa (active enzyme). The active, 48-kDa, form of VCP is maximally present at the middle of embryonic development and disappears by the end.

Aedes↗

PubMed2002

Vaccinia virus complement control protein enhances functional recovery after traumatic brain injury.

Inflammation is a major contributor to the neuropathological consequences of traumatic brain injury (TBI). Previous studies have shown that proinflammatory complement activation fragments are present in the injured brain within the first 24 h after trauma. To investigate whether complement activation within the injured brain leads to the neuropathology and subsequent functional impairment associated with TBI, we examined what effect administration of a complement inhibitor, the vaccinia virus complement control protein (VCP), would have on spatial learning and memory in brain injured rats, as measured using the Morris Water Maze (MWM) procedure. Animals were subjected to a lateral fluid percussion brain injury of moderate severity and, 15 min later, received a 10-microL injection of either full-length VCP, a truncated version of VCP (VCPt), which lacks the complement inhibitory activity but retains the heparin binding activity of VCP, or saline directly into the cortex. Results of such intervention indicated that, at 2 weeks postinjury, both VCP and VCPt treatment attenuated impairments in spatial memory, but not neuropathological damage, as compared to the saline treated controls. These results were surprising and suggest that the neuroprotective effects following administration of VCP after acute brain injury are mediated by mechanisms other than complement inhibition. Potential mechanisms are discussed.

Animals↗

PubMed1984

Efferent role of ADH in CNS-induced natriuresis.

Ventriculocisternal perfusion (VCP) of artificial cerebrospinal fluid (CSF) was performed in pentobarbital-anesthetized dogs. Renal function was studied in protocols consisting of a 1-h experimental period in which the animals received either CSF with an elevated sodium concentration (300 mM, high Na) via VCP or antidiuretic hormone (ADH) intravenously, bracketed by 1-h control and recovery periods. High Na VCP caused an increase in plasma ADH measured by radioimmunoassay (to 176% of control) that coincided with a natriuresis (to 180% of control). In a second set of experiments, these changes in endogenous ADH were mimicked experimentally with intravenous infusions of synthetic ADH in animals receiving continuous VCP with normal sodium artificial CSF. The dose-response relationship between log ADH and urinary sodium excretion for the intravenous ADH experiments was not different from the relationship for those experiments in which ADH was elevated as a consequence of high Na VCP. These results suggest that ADH causes part, if not all, the natriuresis induced by high Na VCP.

Animals↗

PubMed1992

Role of glutamate as the central neurotransmitter in the hypoxic ventilatory response.

Recent data suggest that the increase in ventilation during hypoxia may be related to the release of the excitatory amino acid neurotransmitter glutamate centrally. To further investigate this, we studied the effects of MK-801, a selective noncompetitive N-methyl-D-aspartate receptor antagonist, on the hypoxic ventilatory response in lightly anesthetized spontaneously breathing intact dogs. The cardiopulmonary effects of sequential ventriculocisternal perfusion (VCP) at the rate of 1 ml/min with mock cerebrospinal fluid (CSF, control) and MK-801 (2 mM) were compared during normoxia and 8 min of hypoxic challenge with 12% O2. Minute ventilation (VE), tidal volume (VT), and respiratory frequency (f) were recorded continuously, and hemodynamic parameters [heart rate (HR), blood pressure (MAP), cardiac output (CO), pulmonary arterial pressure, and pulmonary capillary wedge pressure] were measured periodically. Each dog served as its own baseline control before and after each period of sequential VCP under the two different O2 conditions. During 15 min of normoxia, there were no significant changes in the cardiopulmonary parameters with mock CSF VCP, whereas with MK-801 VCP for 15 min, VE decreased by approximately 27%, both by reductions in VT and f (17 and 9.5%, respectively). HR, MAP, and CO were unchanged. During 8 min of hypoxia with mock CSF VCP, VE increased by 171% associated with increased VT and f (25 and 125%, respectively). HR, MAP, and CO were likewise augmented. In contrast, the hypoxic response during MK-801 VCP was characterized by an increased VE of 84%, mainly by a rise in f by 83%, whereas the VT response was abolished. The cardiovascular excitation was also inhibited.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2005

Valosin-containing protein phosphorylation at Ser784 in response to DNA damage.

The response of eukaryotic cells to DNA damage includes the activation of phosphatidylinositol-3 kinase-related kinases (PIKK), such as ATM, ATR, and DNA-dependent protein kinase (DNA-PK). These three kinases have very similar substrate specificities in vitro, but in vivo, their substrates overlap only partially. Several in vivo substrates of ATM and ATR have been identified and almost all of them are involved in DNA damage-induced cell cycle arrest and/or apoptosis. In contrast, few in vivo substrates of DNA-PK have been identified. These include histone H2AX and DNA-PK itself. We identify here valosin-containing protein (VCP) as a novel substrate of DNA-PK and other PIKK family members. VCP is phosphorylated at Ser784 within its COOH terminus, a region previously shown to target VCP to specific intracellular compartments. Furthermore, VCP phosphorylated at Ser784 accumulated at sites of DNA double-strand breaks (DSBs). VCP is a protein chaperone that unfolds and translocates proteins. Its phosphorylation in response to DNA damage and its recruitment to sites of DNA DSBs could indicate a role of VCP in DNA repair.

Adenosine Triphosphatases↗

PubMed2006

Valosin-containing protein gene mutations: clinical and neuropathologic features.

BACKGROUND: Hereditary inclusion body myopathy (IBMPFD) with Paget disease of bone (PDB) and frontotemporal dementia (FTD) is a rare multisystem disorder with autosomal dominant inheritance. Recently, missense mutations in the gene encoding valosin-containing protein (VCP) have been found in individuals with IBMPFD. VCP/P97, which exerts a variety of cellular functions, plays a key role in the ubiquitin-proteasome dependent degradation of cytosolic proteins and in the retrotranslocation of misfolded proteins from the endoplasmic reticulum into the cytoplasm. METHODS: The authors describe the clinical features of two kindreds in which VCP R93C and R155C missense mutations segregate and perform a histopathologic examination of brain, muscle, bone, and liver of three subjects harboring the R155C mutation. RESULTS: Frontotemporal dementia was present in 100% of affected subjects in Family F1 and 70% in Family F2, as compared with an average of 30% in previously described IBMPFD families. In contrast, PDB was a more inconstant clinical feature. Biochemical and histopathologic data are consistent with the hypothesis that VCP R155C mutation disrupts normal VCP function, leading to diffuse accumulation of ubiquitinated proteins within the cells. CONCLUSIONS: VCP mutations are present in two families in which FTD is the most prominent symptom. The histopathologic study performed in patients harboring the R155C mutation supports the hypothesis that this mutation disrupts normal VCP function, leading to diffuse accumulation of ubiquitinated proteins within the cells. IBMPFD belongs to a class of genetic diseases associated with an alteration of the ubiquitin-proteasome system.

Adenosine Triphosphatases↗

PubMed2003

RNA interference of valosin-containing protein (VCP/p97) reveals multiple cellular roles linked to ubiquitin/proteasome-dependent proteolysis.

We have used RNA interference (RNAi) to examine the functional relationship between valosin-containing protein (VCP/p97/Cdc48p/TER94) ATPase and the ubiquitin-proteasome system (UPS) in Drosophila S2 and human HeLa cells. In both cell types, RNAi of VCP (and, to a lesser extent, of certain VCP-interacting proteins) caused significant accumulation of high-molecular-weight conjugates of ubiquitin, an indication of inhibited UPS function. However, decreased VCP levels did not directly inhibit proteasome activity. In HeLa cells, polyubiquitinated proteins accumulated as dispersed aggregates rather than as single aggresomes, even in the presence of proteasome inhibitors, which normally promote aggresome formation. RNAi of VCP caused extensive vacuolization of the cytoplasm, and proteasome inhibitors exaggerated this feature. RNAi of VCP had little effect on S2 cell proliferation but blocked cell-cycle progression and induced mitotic abnormalities and apoptosis in HeLa cells. These results indicate that VCP plays an important general role in mediating the function of the UPS, probably by interacting with potential proteasome substrates before they are degraded by the proteasome.

Adenosine Triphosphatases↗

PubMed2006

Structure and regulatory profile of the monkeypox inhibitor of complement: comparison to homologs in vaccinia and variola and evidence for dimer formation.

The outbreak of monkeypox in the Unites States in the summer of 2003 was the first occurrence of this smallpox-like disease outside of Africa. This limited human epidemic resulted from cross-infection of prairie dogs by imported African rodents. Although there were no human fatalities, this outbreak illustrates that monkeypox is an emerging natural infection and a potential biological weapon. We characterized a virulence factor expressed by monkeypox (monkeypox inhibitor of complement enzymes or MOPICE). We also compared its structure and regulatory function to homologous complement regulatory proteins of variola (SPICE) and vaccinia (VCP). In multiple expression systems, 5-30% of MOPICE, SPICE, and VCP consisted of function-enhancing disulfide-linked homodimers. Mammalian cells infected with vaccinia virus also expressed VCP dimers. MOPICE bound human C3b/C4b intermediate to that of SPICE and VCP. Cofactor activity of MOPICE was similar to VCP, but both were approximately 100-fold less efficient than SPICE. SPICE and VCP, but not MOPICE, possessed decay-accelerating activity for the C3 and C5 convertases of the classical pathway. Additionally, all three regulators possessed heparin-binding capability. These studies demonstrate that MOPICE regulates human complement and suggest that dimerization is a prominent feature of these virulence factors. Thus, our data add novel information relative to the functional repertoire of these poxviral virulence factors. Furthermore, targeting and neutralizing these complement regulatory active sites via mAbs is a therapeutic approach that may enhance protection against smallpox.

Amino Acid Sequence↗

PubMed1999

Central modules of the vaccinia virus complement control protein are not in extensive contact.

The 28.6 kDa vaccinia virus complement control protein (VCP) is an inhibitor of the complement system and has therapeutic potential. It is composed of four domains or modules and is a homologue of complement receptor 1 (CR1) and other mammalian regulators of complement activation. A key aspect to structure-function relationships in these proteins is the extent of intramolecular module-module interactions, since these dictate the overall shape and flexibility of the molecules. A protein fragment (VCP approximately 2,3) encompassing modules 2 and 3 of VCP was over-expressed in Pichia pastoris. Ultracentrifugation showed that VCP approximately 2,3 is highly asymmetric with an axial ratio of 5.3:1, which is consistent with an end-to-end arrangement of the two modules. NMR spectroscopy, differential scanning calorimetry, CD and intrinsic tryptophan fluorescence were used to monitor unfolding of VCP approximately 2,3. Experiments performed over a range of temperatures and concentrations of guanidinium chloride revealed that module 2 unfolds under milder conditions than, and independently of, module 3. Unfolding of module 2 is not associated with extensive changes in amide (15)N and (1)H chemical shifts of module 3, implying that the modules do not form an extensive intermodular interface. Results obtained in this work for VCP approximately 2,3 are compared with those obtained in a study of CR1 modules 15-17 [Kirkitadze, Krych, Uhrin, Dryden, Smith, Cooper, Wang, Hauhart, Atkinson and Barlow (1999) Biochemistry 38, 7019-7031].

Amino Acid Sequence↗

PubMed2006

Antibodies to viral citrullinated peptide in rheumatoid arthritis.

OBJECTIVE: To analyze the frequency of anti-viral citrullinated peptide (anti-VCP) antibodies in sera from patients with rheumatoid arthritis (RA) by an Epstein-Barr virus (EBV)-derived peptide in which arginine is replaced with citrulline. METHODS: Anti-VCP antibodies were determined in 627 serum samples, 300 from patients with RA and 327 from controls, including connective tissue diseases, chronic arthritides, and healthy donors. Among patients with RA, a possible correlation with systemic involvement, disease severity, and disease activity was investigated; in 94 RA patients antibodies to cyclic citrullinated protein (anti-CCP) were also measured. RESULTS: Anti-VCP antibodies were found in 45% of RA sera versus less than 5% of controls; anti-VCP levels correlated with anti-CCP levels (p < 0.0001), rheumatoid factor (p = 0.02), and erythrocyte sedimentation rate (p = 0.0058). No correlation was found with extraarticular manifestations of the disease or with disease severity. CONCLUSION: Anti-VCP antibodies are helpful in discriminating RA from other chronic arthritides or connective tissue disorders. The level of positivity is positively correlated with the anti-CCP level, suggesting that VCP can be considered a novel substrate to detect anti-citrullinated peptide/protein antibodies (ACPA). The reactivity of RA-specific antibodies with a viral citrullinated antigen raises questions on the role of EBV in the induction of ACPA.

Adolescent↗

PubMed2001

Solution structure and dynamics of the central CCP module pair of a poxvirus complement control protein.

The complement control protein (CCP) module (also known as SCR, CCP or sushi domain) is prevalent amongst proteins that regulate complement activation. Functional and mutagenesis studies have shown that in most cases two or more neighbouring CCP modules form specific binding sites for other molecules. Hence the orientation in space of a CCP module with respect to its neighbours and the flexibility of the intermodular junction are likely to be critical for function. Vaccinia virus complement control protein (VCP) is a complement regulatory protein composed of four tandemly arranged CCP modules. The solution structure of the carboxy-terminal half of this protein (CCP modules 3 and 4) has been solved previously. The structure of the central portion (modules 2 and 3, VCP approximately 2,3) has now also been solved using NMR spectroscopy at 37 degrees C. In addition, the backbone dynamics of VCP approximately 2,3 have been characterised by analysis of its (15)N relaxation parameters. Module 2 has a typical CCP module structure while module 3 in the context of VCP approximately 2,3 has some modest but significant differences in structure and dynamics to module 3 within the 3,4 pair. Modules 2 and 3 do not share an extensive interface, unlike modules 3 and 4. Only two possible NOEs were identified between the bodies of the modules, but a total of 40 NOEs between the short intermodular linker of VCP approximately 2,3 and the bodies of the two modules determines a preferred, elongated, orientation of the two modules in the calculated structures. The anisotropy of rotational diffusion has been characterised from (15)N relaxation data, and this indicates that the time-averaged structure is more compact than suggested by (1)H-(1)H NOEs. The data are consistent with the presence of many intermodular orientations, some of which are kinked, undergoing interconversion on a 10(-8)-10(-6) second time-scale. A reconstructed representation of modules 2-4 allows visualisation of the spatial arrangement of the 11 substitutions that occur in the more potent complement inhibitor from Variola (small pox) virus.

Amino Acid Sequence↗