Biomedical subjects

S Thiel

Publications and source records attributed to S Thiel.

111 records · Page 7Linked to original sources

PubMedDate not supplied

Mannan-binding protein, a complement activating animal lectin.

Mannan-binding protein is an animal serum lectin (i.e. a molecule with the ability to bind specifically to certain carbohydrate structures). The relevant carbohydrate ligands are found on many pathogenic microorganisms. After binding to suitable carbohydrate ligands, mannan-binding protein is found to be an activator of the classical pathway of complement via an activation of the C1r2C1s2 complex, i.e. antibody and C1q independent. The molecular organization of MBP resembles that of C1q with a distinct division of collagen-like and globular amino acid sequences. This molecular similarity seems to be the basis for the common functional activity of the two proteins. MBP may play an important protective role, especially at early stages of infection prior to the generation of the specific humoral and cellular defence system. The paper explores the structure and the physiological functions of mannan-binding protein.

Animals↗

PubMedDate not supplied

Delineation of selective cyclic GMP-dependent protein kinase Ialpha substrate and inhibitor peptides based on combinatorial peptide libraries on paper.

Peptide libraries on cellulose paper have proven to be valuable tools for the a priori determination of substrate specificities of cyclic AMP- and cyclic GMP-dependent protein kinases (cAMP-kinase and cGMP-kinase) on the basis of octa-peptide sequences. Here, we report the extension of our peptide library screens to 12-mer and 14-mer peptide sequences, resulting in highly cGMP-kinase Ialpha selective peptides. The sequences TQAKRKKSLAMA-amide and TQAKRKKSLAMFLR-amide, with Km values for cGMP-kinase Ialpha of 0.7 and 0.26 microM and Vmax values of 11.5 and 10.9 micromol/min/mg, respectively, display a high specificity for this enzyme. Furthermore, replacing the phosphate acceptor residue serine with alanine in TQAKRKKSLAMA-amide resulted in the highly cGMP-kinase Ialpha selective inhibitor peptide TQAKRKKALAMA-amide, with inhibitor constants for cGMP-kinase Ialpha and cAMP-kinase of 7.5 microM and 750 microM, respectively. Selective cGMP-kinase inhibitors have the potential to play an important role in the elucidation of the distinct cellular functions of cGMP-kinase separate from those activated by cAMP-kinases, and, therefore, may play an important role as pharmaceutical targets. Molecular docking experiments of the most cGMP-kinase selective sequences on a molecular model of the catalytic domain of cGMP-kinase Ialpha suggest that they adopt unique conformations, which differ significantly from those observed for the cAMP-kinase-specific inhibitor PKI(5-24). Our results suggest that despite their structural similarities, cAMP-kinase and cGMP-kinase use distinct peptide substrate and inhibitor conformations, which could account for their unique substrate specificities. These findings are further supported by cAMP- and cGMP-kinase-selective inhibitor analogs with (D)-Ala residues at the inhibitory positions.

Animals↗

PubMedDate not supplied

Mannan-binding lectin and RSV lower respiratory tract infection leading to hospitalization in children: a case-control study from Soweto, South Africa.

Respiratory syncytial virus (RSV) is the most important microbiological cause of lower respiratory tract infection (LRTI) in infants. Mannan-binding lectin (MBL) is believed to play a major protective role in the vulnerable period in infancy where the maternal antibodies have been catabolized, and the adaptive immune system has not yet matured. Mutations in the promoter region and in exon 1 of the gene-encoding MBL result in low serum levels of MBL. MBL deficiency is the most common immunodeficiency on the African Continent with frequencies of the variant alleles up to 0.29. We investigated whether MBL deficiency has an impact on the hospitalization for LRTI caused by RSV in infants from Soweto, South Africa. The cases were ethnic black Africans identified through surveillance for RSV-LRTI at Chris Hani Baragwanath Hospital, Soweto, and the controls were sampled from four immunization clinics in the area. Fifty-five cases and 113 age- and sex-matched controls were identified. Seventy-six per cent were under 6 months of age, and 42% (n = 23) were under 3 months of age. No association was found between low levels of MBL or carriage of variant alleles and LRTI caused by RSV, odds ratio (OR) 1.00 (CI 0.99-1.03) and OR 1.24 (0.73-2.12). We did not find support for the hypothesis that MBL deficiency leads to the hospitalization for LRTI caused by RSV.

Case-Control Studies↗