The specificity of binding of glycoprotein hormones to their receptors

The glycoprotein hormone receptor family is peculiar because, in contrast to other G protein-coupled receptors, a large N-terminal extracellular ectodomain is responsible for hormone recognition. Hormone-receptor pairs have evolved in such a manner that a limited number of positions both at the 'seat-belt' domain of the hormone and the leucine-rich repeats of the receptor, play attractive and repulsive interactions for binding and specificity, respectively. Surprisingly, the constitutive activity of the receptor, mostly modulated by highly conserved amino acids within the heptahelical domain of the receptor (i.e., outside the hormone binding region), also regulates effectiveness of hormone recognition by the extracellular part. In this review we analyze, at the molecular level, these important discriminating determinants for selective binding of glycoprotein hormones to their receptors, as well as natural mutations, observed in patients with gestational hyperthyroidism or ovarian hyperstimulation syndrome, that modify the selectivity of binding.     

A paper strip electrophoretic examination of the action of dextran in colloidal solution on human serum

Zusammenfassung Eine 6% ige kolloidale Dextranlösung,in vivo infundiert oder dem Serumin vitro zugesetzt ändert dessen Lipidogramm. Zwischen Startpunkt und -Globulinen entsteht eine neue mit DL bezeichnete Fettfraktion. Im Verlauf der Experimente unterblieb eine Trübung des Serums und Änderung des Elektrophorese-Proteinogramms.     

Selection of cell lines resistant to cyclic AMP and theophylline from murine plasmocytoma MOPC 173. Cross resistance to ouabain and concanavalin A]

Using cAMP or theophyllin as selective agents, we obtained from contact inhibited and non contact inhibited cell lines, derived from the same plasmocytoma, different resistant cell lines. All of them were cAMP and theophyllin resistant and also ouabain and con A resistant as judged by the growth curves in presence of the different drugs.     

Theories of enzyme specificity and their application to proteases and aminoacyl-Transfer RNA synthetases

Summary The question of enzyme specificity which is a corollary of the phenomenon of biological recognition is reviewed. The following theories are outlined briefly: non-productive binding, induced fit, transition state binding, the general strain theory and the kinetic proofreading hypothesis. Data on proteolytic enzymes and aminoacyl-tRNA synthetases are discussed in the light of predictions made by the various theories. The specificity of inhibitor and substrate binding to chymotrypsin and subtilisins is revealed at the sub-molecular level as an example of binding specificity. Kinetic specificity is experimentally distinguished from binding specificity. Conformational adaptability of enzyme and substrate, which is crucial in some theories, is documented by data on aminoacyl-tRNA synthetases. Expected and observed specificity of tRNA charging is discussed with regard to a theoretical limit of specificity. Additional means seem necessary beside those contained in the isolated enzyme-substrate system to account for the high specificity of most synthetases. In conclusion, we have arrived at quite good explanations for moderate specificity such as is displayed by many proteases, but there are still ample difficulties in the understanding of highly specific enzyme reactions.Dedicated to the memory of the late ProfessorJosef Rudinger.I acknowledge a fellowship by the Schweizerischer Nationalfonds which I received while doing much of my own work cited in this article.     

The relationship of phosphate and lipids to xanthine dehydrogenase

Résumé La xanthine déshydrogénase, enzyme du foie de rat, a été obtenue par 2 procédés différents: (a) avec et (b) sans traitement par le Butanol. La teneur totale en phosphore des 2 préparations a été etonnament élevée. Soixante %, à peu près, du phosphore total s'est montré soluble dans des solvents de lipides. Certaines hypothèses sur la participation des phosphates et des lipides sur l'activité de l'enzyme sont discutées.

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This paper is derived from a thesis submitted for the degree of Doctor of Biochemistry at the Federal University of Rio de Janeiro and was supported by grants from Conselho Nacional de Pesquisas (Brazil).     

The lipids of human peripheral lymph

Zusammenfassung Fettgehalt und -zusammensetzung der peripheren Lymphe von 14 Patienten wurden untersucht und mit früheren Ergebnissen an peripherem Blut und Thoracicuslymphe verglichen. Der Triglyceridgehalt der Lymphe war grösser, der aller anderen Fettfraktionen niedriger als im peripheren Blut. Zusätzlich wiesen die Triglyceride der Lymphe einen relativ hohen, die Cholesterolester einen relativ tiefen Gehalt an Polyensäuren auf.     

The specificity of histones in nucleated erythrocytes

Riassunto Dagli eritrociti del pollo, dellaRana cateasbeiana e del pesceCaranx hippos sono stati isolati gli istoni nella ipotesi che gli eritrociti forniti di nucleo contengano una frazione di istone funzionante come repressore permanente della sintesi degli acidi nucleici. Detti istoni sono stati frazionati ed analizzati nella loro composizione in amino-acidi. In tutte e tre le speci su menzionate è stata trovata una frazione relativamente ricca in lisina, arginina, alanina, e serina che è stata denominata F2c. L'assenza di detta frazione negli altri tessuti incluso il midollo osseo indica che la frazione F2c può costituire un repressore genetico permanente.

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This investigation was supported by the U.S. Public HEalth Service Grant No. CA-07746, American Cancer Society Grants E-388 and IN-43-F2, and by the Robert A. Welch Foundation Grant G-138.     

The specificity of histones in chicken erythrocytes

Zusammenfassung Isolierung, qualitative und quantitative Charakterisierung der Histone von Hühnererythrocyten wird beschrieben. Mittels Gelfiltration an Sephadex G 75 wurde eine Fraktion des Histons, charakteristisch für die Hühnererythrocytenzellkerne isoliert und analysiert. Diese Fraktion, als F2c bezeichnet, ist ein Teil des lysinreichen Histons F2, reich an Lysin, Alanin, Serin und Arginin (z.B. 21,0, 15,1, 11,9 und 10,6% respektive). Threonin konnte als N-terminale Aminosäure in dieser Fraktion festgestellt werden.     

The effect ofListeria monocytogenes lipids on immune response to T-dependent and T-independent antigens

Summary The administration ofListeria monocytogenes lipids augmented the humoral immune response to ovalbumin (OVA), polyvinyl pyrrolidone andE. coli lipopolysaccharide, but failed to support the induction of delayed hypersensitivity to OVA.This study was supported by the Polish Academy of Sciences (grant No. 10.5).     

The assembly of lipids into lipoproteins during secretion

Summary The process of assembly and secretion of lipoproteins is discussed with particular reference to the role of lipids. The majority of circulating lipoproteins is produced by the liver (80%) with the remainder being supplied by the intestine. The liver secretes both very low density lipoproteins and high density lipoproteins, but the assembly and secretion of these two types of particles may follow different routes. The major lipid components of lipoproteins are triacylglycerols, cholesterol, cholesterol esters and phospholipids. The biosynthesis of these lipids occurs on membranes of the endoplasmic reticulum, with many of the enzymes also being present in the Golgi; the roles of these two subcellular organelles in the assembly of lipoproteins are discussed. There appears to be a compartmentalization of lipids in cells, such that defined pools, often those newly-synthesized, are preferred, or even required, for lipoprotein assembly. The process of hepatic very low density lipoprotein secretion appears to be regulated by the supply of lipids. Indeed, the synthesis of new lipid may be a major driving force in lipoprotein assembly and secretion.     

From MDR to MXR: new understanding of multidrug resistance systems, their properties and clinical significance

The ATP binding cassette (ABC) superfamily of membrane transporters is one of the largest protein classes known, and counts numerous proteins involved in the trafficking of biological molecules across cell membranes. The first known human ABC transporter was P-glycoprotein (P-gp), which confers multidrug resistance (MDR) to anticancer drugs. In recent years, we have obtained an increased understanding of the mechanism of action of P-gp as its ATPase activity, substrate specificity and pharmacokinetic interactions have been investigated. This review focuses on the functional characterization of P-gp, as well as other ABC transporters involved in MDR: the family of multidrug-resistance-associated proteins (MRP1-7), and the recently discovered ABC half-transporter MXR (also known as BCRP, ABCP and ABCG2). We describe recent progress in the analysis of protein structure-function relationships, and consider the conceptual problem of defining and identifying substrates and inhibitors of MDR. An in-depth discussion follows of how coupling of nucleotide hydrolysis to substrate transport takes place, and we propose a scheme for the mechanism of P-gp function. Finally, the clinical correlations, both for reversal of MDR in cancer and for drug delivery, are discussed.