Structure of co-crystals of tropomyosin and troponin

Troponin, a Ca2+-sensitive complex, regulates the motions of tropomyosin on the thin filaments in many muscles. It has three subunits, each with a different architecture and function: TnC binds Ca2+; TnI binds to actin and inhibits contraction; and TnT binds one complex to each tropomyosin molecule. The troponin complex has an elongated shape with TnC and TnI forming a globular 'head' region and TnT a long (approximately 160 A) 'tail'. TnT binds to two widely separated regions of tropomyosin: the head region of the complex is near Cys 190 of tropomyosin and the tail region is near the overlapping joint that links the tropomyosin molecules into filaments. Here we report the X-ray structure determination at 17 A resolution of glutaraldehyde-treated tropomyosin crystals in which native troponin complex or fragments of TnT have been bound. Our results show that the amino-terminal tail end of TnT spans the head-to-tail joint of the tropomyosin filaments, and that the 'head' region of the whole troponin complex binds approximately 200 A away near residues 150-180 of the tropomyosin molecule.     

DDT-analogs as synergists for DDT

Résumé L'influence de la halogénuration du groupement méthyl dans le di-(p-chlorophényl)-méthyl-carbinol sur l'activité de ce composé comme insecticide ou synergiste du DDT a été étudiée. On essaye de donner une explication rationnelle des faits observés.     

Therapeutic approaches to protein-misfolding diseases

Several sporadic and genetic diseases are caused by protein misfolding. These include cystic fibrosis and other devastating diseases of childhood as well as Alzheimer's, Parkinson's and other debilitating maladies of the elderly. A unified view of the molecular and cellular pathogenesis of these conditions has led to the search for chemical chaperones that can slow, arrest or revert disease progression. Molecules are now emerging that link our biophysical insights with our therapeutic aspirations.     

Gut hormone PYY(3-36) physiologically inhibits food intake

Food intake is regulated by the hypothalamus, including the melanocortin and neuropeptide Y (NPY) systems in the arcuate nucleus. The NPY Y2 receptor (Y2R), a putative inhibitory presynaptic receptor, is highly expressed on NPY neurons in the arcuate nucleus, which is accessible to peripheral hormones. Peptide YY(3-36) (PYY(3-36)), a Y2R agonist, is released from the gastrointestinal tract postprandially in proportion to the calorie content of a meal. Here we show that peripheral injection of PYY(3-36) in rats inhibits food intake and reduces weight gain. PYY(3-36) also inhibits food intake in mice but not in Y2r-null mice, which suggests that the anorectic effect requires the Y2R. Peripheral administration of PYY(3-36) increases c-Fos immunoreactivity in the arcuate nucleus and decreases hypothalamic Npy messenger RNA. Intra-arcuate injection of PYY(3-36) inhibits food intake. PYY(3-36) also inhibits electrical activity of NPY nerve terminals, thus activating adjacent pro-opiomelanocortin (POMC) neurons. In humans, infusion of normal postprandial concentrations of PYY(3-36) significantly decreases appetite and reduces food intake by 33% over 24 h. Thus, postprandial elevation of PYY(3-36) may act through the arcuate nucleus Y2R to inhibit feeding in a gut-hypothalamic pathway.     

The immunopathogenesis of sepsis

Sepsis is a condition that results from a harmful or damaging host response to infection. Many of the components of the innate immune response that are normally concerned with host defences against infection can, under some circumstances, cause cell and tissue damage and hence multiple organ failure, the clinical hallmark of sepsis. Because of the high mortality of sepsis in the face of standard treatment, many efforts have been made to improve understanding of the dysregulation of the host response in sepsis. As a result, much has been learnt of the basic principles governing bacterial-host interactions, and new opportunities for therapeutic intervention have been revealed.     

Specification of limb development in the Drosophila embryo by positional cues from segmentation genes

Limb development in Drosophila requires the activity of a proximo-distal pattern-forming system, in addition to the antero-posterior and dorso-ventral pattern-forming systems that subdivide the embryo. Several lines of genetic evidence indicate that the Distal-less gene plays an important part in specifying proximo-distal positional information. The Distal-less locus encodes a homoeodomain-containing protein, which suggests that Distal-less may exert its activity through differential regulation of subordinate genes. The spatially restricted pattern of Distal-less expression allows direct visualization of the limb primordia during early embryogenesis. Here I report that from their inception, the leg primordia span the parasegment boundary. The segment polarity gene wingless seems to have a key part in defining the positions at which leg primordia will develop along the antero-posterior axis of the embryo. This analysis allows a direct molecular visualization of the compartments that subdivide the limb primordia into discrete developmental domains.     

Interaction of epidermal growth factor with human fibroblasts in culture: an autoradiographic study at the ultrastructural level]

The potent mitogen epidermal growth factor (EGF) binds to specific receptors on human fibroblasts. In the present study we have used a quantitative EM autoradiographic approach to visualize the events involved in the binding process. When 125I-EGF is incubated at 4 degrees C for 120 min, labeled EGF primarily localizes to the plasma membrane of the fibroblast but when incubated at 37 degrees C for 120 min., over 2/3 of the labeled material is internalized by the cell. The internalized radioacitivity is primarily localized to lysomes. These studies demonstrate a temperature-dependent internalization of EGF following initial binding to specific plasma membrane receptors.