A synthetic complement C1q-like peptide selectively interacts with immune complexes

A water-soluble peptide possessing an immune complex selective affinity was synthesized and its primary structure established as: Leu-Glu-Gln-Gly-Glu-Asn-Val-Phe-Leu-Gln-Ala-Thr-Ser-Asp-Asp-Cys. This peptide, designated as C1q-like peptide (CLP), represents a possible immune complex binding epitope of complement C1q. CLP has a hydrophilicity value of 0.21. At 0.5 M, it inhibited by 50% natural human C1q from binding to horseradish peroxidase-rabbit anti-peroxidase immune complex. CLP failed to inhibit Staphylococcus aureus protein A from binding monomeric IgG. When coated to a microplate, CLP showed selective binding to the immune complex, and could be used for application in immunochemical detection of immune complex. © Rapid Science Ltd. 1998     

Electrophoretic polymorphism and molecular structure of equine C3

Plasma or serum samples from 12 Arabian and 181 standardbred horses have been typed using an immunofixation technique to determine electrophoretic polymorphism of equine third complement component (C3). Six distinctly different electrophoretic patterns of equine C3 have been recognized thus far. SDS PAGE analysis of equine C3/anti C3 complexes revealed that the submolecular structure comprised an alpha chain and beta chain of molecular weights approximately 118,000 and 63,000 daltons respectively. The molecular weights of the alpha and beta chains were similar in all electrophoretic variants tested. Family data derived from 73 mares, 21 stallions and 99 offspring suggested that the six electrophoretic phenotypes were inherited by means of three codominant alleles named C3-1, C3-2 and C3-3 at a single autosomal locus.     

Associations of the Polymorphisms in DHRS4, SERPING1, and APOR Genes with Postmortem pH in Berkshire Pigs

Postmortem pH is a main factor influencing the meat quality in pigs. This study investigated the association of postmortem pH with single-nucleotide polymorphisms (SNPs) in the fourth member of the short-chain dehydrogenase/reductase family (DHRS4), the first member of serpin peptidase inhibitor, clade G (complement inhibitor) (SERPING1), and the apolipoprotein R precursor (APOR) genes in Berkshire pigs. The study included 437 pigs, and genotyping was conducted using the GoldenGate Assay (Illumina, San Diego, CA, USA). DHRS4, SERPING1, and APOR polymorphisms were significantly associated with pH₄₅ or pH₂₄ (p?SERPING1 was also statistically significantly associated with water holding capacity (p?DHRS4, SERPING1, and APOR genes have potential for use as genetic markers for the meat quality in pigs.     

Pcp4l1 contains an auto-inhibitory element that prevents its IQ motif from binding to calmodulin

Purkinje cell protein 4-like 1 (Pcp4l1) is a small neuronal IQ motif protein closely related to the calmodulin-binding protein Pcp4/PEP-19. PEP-19 interacts with calmodulin via its IQ motif to inhibit calmodulin-dependent enzymes and we hypothesized Pcp4l1 would have similar properties. Surprisingly, full-length Pcp4l1 does not interact with calmodulin in yeast two-hybrid or pulldown experiments yet a synthetic peptide constituting only the IQ motif of Pcp4l1 binds calmodulin and inhibits calmodulin-dependent kinase II. A nine-residue glutamic acid-rich sequence in Pcp4l1 confers these unexpected properties. This element lies outside the IQ motif and its deletion or exchange with the homologous region of PEP-19 restores calmodulin binding. Conversion of a single isoleucine (Ile36) within this motif to phenylalanine, the residue present in PEP-19, imparts calmodulin binding onto Pcp4l1. Moreover, only aromatic amino acid substitutions at position 36 in Pcp4l1 allow binding. Thus, despite their sequence similarities PEP-19 and Pcp4l1 have distinct properties with the latter harboring an element that can functionally suppress an IQ motif. We speculate Pcp4l1 may be a latent calmodulin inhibitor regulated by post-translational modification and/or co-factor interactions.     

精神分裂症易感基因

精神分裂症是一类遗传倾向性较高的多基因疾病。近年来,随着遗传学和分子生物学为主的多学科研究技术的快速发展,不断有新的易感基因报道;一些重要易感基因的生物学功能及其在该疾病发病机制中的作用研究也取得了一定进展。     

Differences in planning performance,a neurocognitive endophenotype,are associated with a functional variant in PER3 gene

Performance alterations in executive function have been studied as potential endophenotypes for several neuropsychiatric diseases. Planning is an important component of executive function and has been shown to be affected in diseases such as attention deficit hyperactivity disorder, schizophrenia, obsessive–compulsive disorder and Parkinson’s disease. Several genes related to dopaminergic systems, such as COMT, have been explored as candidates for influencing planning performance. The circadian clock gene PERIOD3 (PER3) has been shown to be associated with several complex behaviors in humans and could be involved in different signaling mechanisms. In this study, we evaluated the possible association between a functional polymorphism in the PER3 gene (PER3-VNTR, rs57875989) and performance in a commonly used test of planning (Tower of London, TOL) in 229 healthy subjects from Bogotá, Colombia. PER3-VNTR genotyping was carried out with conventional PCR and all participants completed the TOL test using the computerized Psychology Experiment Building Language (PEBL) battery. A linear regression model was used for the analysis of association with the SNPStats program. We found that 4/4 genotype carriers showed a better performance and made fewer moves, in comparison to 4/5 and 5/5 genotype carriers (p?=?0.003). These results appear to be independent from effects of this polymorphism on self-reported average hours of sleep during work days in our sample. This is the first evidence of an association between PER3-VNTR and planning performance in a sample of healthy subjects and our results are consistent from previous findings for alterations in other cognitive domains. Future studies examining additional genes could lead to the identification of novel molecular underpinnings of planning in healthy subjects and in patients with neuropsychiatric disorders.     

PDE4在DISC1突变诱发的精神分裂症中的作用

精神分裂症断裂基因1(disrupted in schizophrenia 1,DISC1)是多种精神疾病中的一个关键的遗传学危险因素。DISC1能够与磷酸二酯酶4(phosphodiesterase 4,PDE4)相互作用形成复合物,这可能是一些精神疾病的关键分子机制。PDE4能够水解cAMP,DISC1可通过调节PDE4的活性进而发挥调节cAMP在细胞内的信号转导功能。已有研究证实,在一些精神疾病患者中,DISC1和PDE4基因表达均发生了变化。DISC1突变导致其表达产物与PDE4的相互作用减弱,结果之一是降低脑PDE4的活性。DISC1与PDE4之间的相互作用的改变可能是精神分裂症及抑郁症等疾病症状产生的基础。     

DISC1 genetics, biology and psychiatric illness

Psychiatric disorders are highly heritable, and in many individuals likely arise from the combined effects of genes and the environment. A substantial body of evidence points toward DISC1 being one of the genes that influence risk of schizophrenia, bipolar disorder and depression, and functional studies of DISC1 consequently have the potential to reveal much about the pathways that lead to major mental illness. Here, we review the evidence that DISC1 influences disease risk through effects upon multiple critical pathways in the developing and adult brain.     

Regulators of complement activity mediate inhibitory mechanisms through a common C3b‐binding mode

Regulators of complement activation (RCA) inhibit complement‐induced immune responses on healthy host tissues. We present crystal structures of human RCA (MCP, DAF, and CR1) and a smallpox virus homolog (SPICE) bound to complement component C3b. Our structural data reveal that up to four consecutive homologous CCP domains (i–iv), responsible for inhibition, bind in the same orientation and extended arrangement at a shared binding platform on C3b. Large sequence variations in CCP domains explain the diverse C3b‐binding patterns, with limited or no contribution of some individual domains, while all regulators show extensive contacts with C3b for the domains at the third site. A variation of ~100° rotation around the longitudinal axis is observed for domains binding at the fourth site on C3b, without affecting the overall binding mode. The data suggest a common evolutionary origin for both inhibitory mechanisms, called decay acceleration and cofactor activity, with variable C3b binding through domains at sites ii, iii, and iv, and provide a framework for understanding RCA disease‐related mutations and immune evasion.     

Isotyping of component C4 of human complement using differences in the functional activity of isotypes C4A and C4B

The difference in the functional activity of the isotypes A and B of component C4 of human complement was used to determine their ratio and to detect the inherited deficiency of the isotypes. ELISA methods were developed for the quantitative assay of component C4 (conventional sandwich method) and its functional activity. When determining the functional activity, the classic pathway of the complement and therefore of component C4 was activated on activators sorbed on ELISA microplates: immunoglobulin IgG3 or liposaccharide of theShigella sonnei cell walls, which activates the complement by binding component C1. The nascent fragment C4b is covalently bound to the target activator; C4Ab binds better to the target protein (immunoglobulin), and C4Bb to the target carbohydrate (liposaccharide). Therefore, when immunoglobulin is a target activator, isotype C4A is bound and determined; and when the complement is activated with liposaccharide, isotype C4B is determined. The radio of the activities determined by the two methods indicates the deficiency in the individual isotypes of component C4 or its absence. The rabbit polyclonal monospecific antibodies against the human component C4 and the conjugates of these antibodies with horseradish peroxidase were used in the methods described.