Disease relevance of C4BPA

• We show that the elevation of C4BP during acute phase response leads to changes in the proportion of the C4BP isoforms [1].
• After screening several malignant cell lines, we observed that the ovarian adenocarcinoma cell lines SK-OV-3, Caov-3, and SW626 were capable of binding C4bp [2].
• In the present report we demonstrate that isolated type IV pili from Neisseria gonorrhoeae bind human C4BP in a dose-dependent and saturable manner [3].
• Bacteriophage binding to the beta-chain of C4BP were selected in several rounds of affinity purification with intervening amplification in E. coli [4].
• Identification of a portion of protein S that binds to C4BP has been approached using random libraries of 6- and 15-mer peptides displayed on bacteriophage surfaces [4].

Psychiatry related information on C4BPA

• We used immunochemical methods to demonstrate C4BP in brains of subjects with Alzheimer's disease and normal controls [5].
• Colostrinin (CLN) is a biologically active proline-rich polypeptide which has therapeutic potential for the alleviation of memory deficits in age-related dementias in a number of human conditions, particularly Alzheimer's disease [6].
• The uptake kinetics of serotonin (5-HT) in platelets from eight patients with endogenous depression was determined in platelet rich plasma (PRP) [7].
• We explore whether the conflict resolution of the Stroop and flanker tasks is different as well by embedding these two tasks in a PRP (Psychological Refractory Period) paradigm [8].
• Two-hundred and seventy-one 11- and 12-year-olds, with elevated depressive symptoms, were randomized to PRP or usual care [9].

High impact information on C4BPA

• A common RXL motif was found in proline-rich ligands that were selected from a biased combinatorial peptide library on the basis of their ability to bind specifically to the SH3 domains from phosphatidylinositol 3-kinase (PI3K) or c-Src [10].
• The 856 amino acid open reading frame contains five Krüppel-type zinc finger motifs and proline-rich and acidic regions similar to those of known transcription factors [11].
• We conclude that SH3 domains recognize proline-rich motifs possessing the left-handed type II polyproline (PPII) helix conformation [10].
• WASP encodes a 501 amino acid proline-rich protein that is likely to be a key regulator of lymphocyte and platelet function [12].
• Elicitor- and wound-induced oxidative cross-linking of a proline-rich plant cell wall protein: a novel, rapid defense response [13].

Chemical compound and disease context of C4BPA

• AIMS: To study protein S, as an acute phase protein, for its relationships with C4b-BP (C4BP), fibrinogen and Factor VIII:C in a group of patients with solid tumours, without proven metastases [14].
• These findings suggest that the C4 activation process as well as the regulation process of C system and of the inflammatory coagulation axis by C4bp and PS may play an important role in the pathophysiology of preeclampsia, so-called glomerular capillary endotheliosis (GCE) [15].
• Haemophilus influenzae type b (Hib) capsular polysaccharide (PRP) was selectively hydrolyzed to reducing oligosaccharides, and the fraction containing 3-10 ribosylribitolphosphate repeating units (VS) was conjugated by reductive amination to diphtheria toxin (DTx), its nontoxic derivative CRM197 (Dcr), or diphtheria toxoid (DTd) [16].
• A serine/proline-rich protein is fused to HRX in t(4;11) acute leukemias [17].
• To further elucidate the mechanisms of hypoglycemia-induced platelet activation, we incubated in vitro platelet-rich plasma (PRP) of seven fasting healthy subjects with the same concentrations of insulin, epinephrine, glucagon, growth hormone, and cortisol measured in vivo during insulin-induced hypoglycemia [18].

Biological context of C4BPA

• Finally, linkage analysis with 4 microsatellite markers linked to the C4BPB and C4BPA loci also excluded these two genes [19].
• Dinucleotide repeat polymorphism between the human C4BPA and C4BPB gene loci (1q32) [20].
• We speculate that this extreme requirement of HNF1 for the activity of the human C4BPA promoter is related to the fact that this promoter lacks a TATA box [21].
• We found that the C4BPA promoter is contained within the first 369 bp upstream of the transcription start site [21].
• We report here the characterization of C4BPAL1, a member of the human RCA gene cluster that arose from the duplication of the C4BPA gene after the separation of the rodent and primate lineages [22].

Anatomical context of C4BPA

• Membrane cofactor protein, previously shown to be a receptor for pathogenic N. gonorrhoeae on the surface of epithelial cells, competed with C4BP for binding to pili only at high concentrations, suggesting that different parts of pili are involved in these two interactions [3].
• The interaction of protein S with membranes and subsequent combination with complement C4b-binding protein (C4BP) was studied [23].
• Accordingly, high concentrations of C4BP were required to inhibit binding of N. gonorrhoeae to Chang conjunctiva cells, and no inhibition of binding was observed with cervical epithelial cells [3].
• Using hybridoma technology, a panel of monoclonal antibodies (mAb) specific for intact human C4BP and its 160-kDa chymotryptic central core fragment were prepared to study the structure-function relationships of C4BP [24].
• It has been demonstrated in the past that protein S and C4BP can bind to neutrophils [25].

Associations of C4BPA with chemical compounds

• C4b-binding protein (C4bp) participates in the regulation of the C3 convertase of the classical pathway of complement [26].
• C4b-binding protein (C4BP) is an abundant oligomeric plasma glycoprotein which controls the activation of the complement cascade through the classical pathway [21].
• EDTA, heparin, and phosphorylethanolamine as well as a peptide comprising amino acids 27-39 of SAP were found to completely displace C4BP from the SAP matrix [27].
• C4b-binding protein (C4BP) inhibits all pathways of complement activation, acting as a cofactor to the serine protease factor I (FI) in the degradation of activated complement factors C4b and C3b [28].
• Recombinant C4BP composed of only alpha-chains bound SAP with similar affinity (Kd = 22 nM), whereas nonglycosylated recombinant alpha-chain C4BP (synthesized in the presence of tunicamycin) bound SAP with lower affinity (Kd = 126 nM) [27].

Physical interactions of C4BPA

• Available experimental data suggest the beta-chain to contain the single protein S binding site on C4BP, whereas each of the alpha-chains contains a binding site for the complement protein, C4b [29].
• In conclusion, our data demonstrate that the alpha-chains of C4BP comprise a binding site for LRP [30].
• When measured by sucrose density gradient ultracentrifugation, complete dissociation of the complex of hSAP (human SAP) with C4b-binding protein (C4BP) occurred at > or = 5 mM lactate [31].
• Sequencing of amino-terminal and internal peptides from the C3-binding protein disclosed a proline-rich region spanning approximately 20 amino acids and a signal peptide that had not been previously reported [32].
• The plasma concentrations of protein S, protein C and C4b-binding protein (C4BP) were analysed during pregnancy, in the postpartum period and in women using oral contraceptives [33].

Enzymatic interactions of C4BPA

• These domains bind to proteins containing proline-rich regions or tyrosine-phosphorylated proteins and contribute to the association of Grb2/Ash and Shc with other signaling molecules [34].
• In addition, I alone or in the presence of C4-bp fails to cleave the alpha 1-chain of C4b in the stabilized C4b, 2a complex [35].

Regulatory relationships of C4BPA

• Further analysis showed that association of rC4BPalpha to LRP was inhibited by heparin or by anti-C4BP antibody RU-3B9, which recognizes the heparin-binding region of the C4BP alpha-chains [30].
• It was suggested that the metabolism of C4bp might be regulated by the plasma PS level, although this hypothesis needs further exploration [36].
• Dynamin GTPase is stimulated by crosslinking through the C-terminal proline-rich domain [37].
• Finally, an equivalent N-terminal fragment of PI3K-C2alpha that lacks similar proline-rich motifs was unable to affinity purify the activated EGF receptor from cell lysates [38].
• The binding of VEGF-B(167) was mediated by the heparin binding domain, whereas the binding of VEGF-B(186) to NRP1 was regulated by exposure of a short COOH-terminal proline-rich peptide upon its proteolytic processing [39].

Other interactions of C4BPA

• From these results we conclude that, at least in some families, the molecular basis of type III PS deficiency is not due to the Mendelian inheritance of a single defect in the PROS1 or in the C4BP genes [19].
• C4BPAL1 maps 20 kb downstream of the C4BPA gene and is the same 5' to 3' orientation found for all RCA genes characterized thus far [22].
• C4BPAL2: a second duplication of the C4BPA gene in the human RCA gene cluster [40].
• It contains two exons homologous to the exons coding for the SCR-1 and SCR-2 repeats of the human C4BP beta polypeptide chain [41].
• We propose that LRP mediates at least in part the catabolism of C4BP and, as such, may regulate C4BP participation in complement and hemostatic processes [30].

Analytical, diagnostic and therapeutic context of C4BPA

• C4bp, C4b, and protein S were visualized by electron microscopy by negative staining [26].
• Sequence analysis of the C4BPB exons in the Mus musculus inbred strains CBA, Balb/c, and C57BL/6, in pen-bred Swiss mice, and in Mus spretus demonstrated the presence of two in-phase stop codons that are incompatible with the expression of a functional C4BP beta polypeptide [41].
• Using pulsed field gel electrophoresis analysis we demonstrate that the genes coding for the alpha (C4BP alpha) and beta (C4BP beta) chains are closely linked within the regulator of complement activation gene cluster [42].
• C4BP beta chain antigen levels, measured using a new ELISA, averaged 218 nmol/L, a value indistinguishable from the molar concentrations of bound protein S (215 nmol/L) and bound C4BP (227 nmol/L) [43].
• In a quantitative affinity chromatography assay, the dissociation constants for binding of intact C4BP and of the 160-kDa central core fragment to SAP were found to be 30 and 70 nM, respectively [27].

References