Vitamin K-dependent blood coagulation proteins form hetero-dimers

The later stages of the blood coagulation cascade are characterized by the presence of vitamin K-dependent proteins and their involvement in membrane-bound, multi-protein converting complexes with an essential requirement for calcium ions. Specific interactions between zymogens and activating enzymes have not yet been identified. Here we describe a crystallographic study of prothrombin fragment 1 (residues 1-156 of prothrombin) which indicates that vitamin K-dependent coagulation proteins have specific association sites that allow them to form hetero-dimers. The calcium-induced formation of a hetero-dimer between fragment 1 and factor X is demonstrated by cross-linking. Such hetero-dimers of vitamin K-dependent proteins could be significant in the coagulation system.     

Clindamycin and lincomycin alter miniature endplate current decay.

Antibiotic-induced muscle paralysis has frequently been found in both experimental animals and man with three distinct classes of antibiotic: (1) streptomycin and related aminoglycoside compounds, (2) polymyxins and (3) tetracyclines. Recently lincomycin and its chemical congener, clindamycin, have been reported to produce muscle paralysis which has different characteristics from those seen with other classes of antibiotic. Although closely related in chemical structure, lincomycin and clindamycin also seem to produce muscle paralysis by different mechanisms. Clindamycin is considered to exert a direct depressant action on muscle contractility whereas the action of lincomycin is considered to be primarily a depression of neuromuscular transmission. We report here that each of these antibiotics had a significant but different influence on endplate channel behaviour. Clindamycin increased the rate of miniature endplate current (m.e.p.c.) decay and reduced its voltage sensitivity without altering its exponential nature. Lincomycin split m.e.p.c. decay into an initial rapid phase followed by a prolonged phase.     

Human nutrition, the gut microbiome and the immune system

Marked changes in socio-economic status, cultural traditions, population growth and agriculture are affecting diets worldwide. Understanding how our diet and nutritional status influence the composition and dynamic operations of our gut microbial communities, and the innate and adaptive arms of our immune system, represents an area of scientific need, opportunity and challenge. The insights gleaned should help to address several pressing global health problems.     

The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita

Dyskeratosis congenita is a progressive bone-marrow failure syndrome that is characterized by abnormal skin pigmentation, leukoplakia and nail dystrophy. X-linked, autosomal recessive and autosomal dominant inheritance have been found in different pedigrees. The X-linked form of the disease is due to mutations in the gene DKC1 in band 2, sub-band 8 of the long arm of the X chromosome (ref. 3). The affected protein, dyskerin, is a nucleolar protein that is found associated with the H/ACA class of small nucleolar RNAs and is involved in pseudo-uridylation of specific residues of ribosomal RNA. Dyskerin is also associated with telomerase RNA (hTR), which contains a H/ACA consensus sequence. Here we map the gene responsible for dyskeratosis congenita in a large pedigree with autosomal dominant inheritance. Affected members of this family have an 821-base-pair deletion on chromosome 3q that removes the 3' 74 bases of hTR. Mutations in hTR were found in two other families with autosomal dominant dyskeratosis congenita.