Nuclear transport mechanisms

The term nuclear transport, refers to the movement of a large variety of macromolecules both into and out of the nucleus. Transport must be extremely selective, yet also very efficient. A single type of channel, the nuclear pore complex, mediates all movement across the nuclear envelope. Selectivity is achieved through the use of families of soluble factors that target substrates for import and export and deliver them to their appropriate intracellular destinations. We now have a fairly detailed understanding of the basic mechanisms of protein import into the nucleus. Many of these same principles can be applied to protein export and perhaps RNA export. This review will summarize the current status of what is known about various transport pathways and highlight the questions that remain to be answered.     

Specific transport mechanisms in the erythrocyte membrane

Zusammenfassung Es wird die Entwicklung, die zum Konzept des Trägermechanismus geführt hat, dargestellt. Besonderheiten dieses Transportmechanismus durch die Membran (zum Teil in Analogie zur Enzymkinetik, zum Teil abweichend) werden an Beispielen des Zuckertransports durch die Erythrozytenmembran diskutiert. Schliesslich wird der aktive Transport im Sinne einer Stoffbewegung entgegen dem Aktivitätsgradienten an zwei Beispielen erläutert, die am Erythrozyten studiert wurden: an der Kalium-Natrium-Pumpe und am Aminosäuretransport durch die Membran. In bezug auf ihre Deutung im Sinne von Trägermechanismen wild darauf hingewiesen, dass der einfache Trägertransport durch verschiedene Arten von Kopplung zu einer «Pumpe» mit Aufwärtstransport umgestaltet werden kann.     

Insights into the genetic basis of congenital heart disease

Cardiovascular malformations are the most common type of birth defect and result in significant mortality worldwide. The etiology for the majority of these anomalies remains unknown. Advances in the characterization of the molecular pathways critical for normal cardiac development have led to the identification of numerous genes necessary for this complex morphogenetic process. This work has aided the discovery of an increasing number of single genes being implicated as the cause of human cardiovascular malformations. This review summarizes normal cardiac development and outlines the recent discoveries of the genetic causes of congenital heart disease. Received 4 November 2005; received after revision 14 January 2006; accepted 1 February 2006     

Insights into acylphosphatase structure and catalytic mechanism

Acylphosphatase is one of the smallest enzymes known (about 98 amino acid residues). It is present in organs and tissues of vertebrate species as two isoenzymes sharing over 55% of sequence homology; these appear highly conserved in differing species. The two isoenzymes can be involved in a number of physiological processes, though their effective biological function is not still certain. The solution and crystal structures of different isoenzymes are known, revealing a close packed protein with a fold similar to that shown by other phosphate-bind ing proteins. The structural data, together with an extended site-directed mutagenesis investigation, led to the identification of the residues involved in enzyme catalysis. However, it appears unlikely that these residues are able to perform the full catalytic cycle: a substrate-assisted catalytic mechanism has therefore been proposed, in which the phosphate moiety of the substrate could act as a nucleophile activating the catalytic water molecule. Received 12 November 1996; accepted 27 November 1996     

Melatonin transport into mitochondria

Melatonin is a well-known, nighttime-produced indole found in bacteria, eukaryotic unicellulars, animals or vascular plants. In vertebrates, melatonin is the major product of the pineal gland, which accounts for its increase in serum during the dark phase, but it is also produced by many other organs and cell types. Such a wide distribution is consistent with its multiple and well-described functions which include from the circadian regulation and adaptation to seasonal variations to immunomodulatory and oncostatic actions in different types of tumors. The discovery of its antioxidant properties in the early 1990s opened a new field of potential protective functions in multiple tissues. A special mention should be made regarding the nervous system, where the indole is considered a major neuroprotector. Furthermore, mitochondria appear as one of the most important targets for the indole’s protective actions. Melatonin’s mechanisms of action vary from the direct molecular interaction with free radicals (free radical scavenger) to the binding to membrane (MLT1A and MLT1B) or nuclear receptors (RZR/RORα). Receptor binding has been associated with some, but not all of the indole functions reported to date. Recently, two new mechanisms of cellular uptake involving the facilitative glucose transporters GLUT/SLC2A and the proton-driven oligopeptide transporter PEPT1/2 have been reported. Here we discuss the potential importance that these newly discovered transport systems could have in determining the actions of melatonin, particularly in the mitochondria. We also argue the relative importance of passive diffusion vs active transport in different parts of the cell.     

Axoplasmic organelles: Quantitative differences between ventral and dorsal root fibres of the rat

Zusammenfassung Motorische und sensible Nervenfasern lassen sich im Bereich der Rückenmarkswurzeln (Ratte, L₅) aufgrund der Mengenverteilung der Axonorganellen unterscheiden. Bei vergleichbarem Faserkaliber haben Vorderwurzelfasern signifikant mehr Neurotubuli und axoplasmatisches Retikulum als Hinterwurzelfasern.

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This investigation was supported by the Fonds zur Förderung der wissenschaftlichen Forschung in Österreich.

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The authors gratefully acknowledge the excellent technical assistance of MissL. Henning and MissB. Fritsche.     

New insights into the molecular mechanisms of sperm-egg interaction

At the moment of insemination millions of mammalian sperm cells are released into the female reproductive tract in order to find a single cell – the oocyte. The spermatozoa subsequently ignore the thousands of cells they make contact with during their journey to the site of fertilisation, until they reach the surface of the oocyte. At this point, they bind tenaciously to the acellular coat, known as the zona pellucida, that surrounds the oocyte and initiate the chain of cellular interactions that will culminate in fertilization. These exquisitely cell- and species-specific recognition events are among the most strategically important cellular interactions in biology. Understanding the cellular and molecular mechanisms that underpin them has implications for diagnosis of the aetiology of human infertility and the development of novel targets for fertility regulation. Herein, we describe two models indicating the plethora of highly orchestrated molecular interactions underlying successful sperm zona binding and sperm oocyte fusion. Received 17 December 2006; received after revision 31 January 2007; accepted 16 March 2007     

A possible mechanism for uptake of biogenic amines by storage organelles: Incorporation into nucleotide-metal aggregates

Zusammenfassung Analytische Ultrazentrifugation ergibt, dass Adenosin-5-triphosphat und Guanosin-5-triphosphat in Gegenwart von Ca und Mg hochmolekulare Aggregate bilden. Die scheinbaren mittleren Molekulargewichte dieser Aggregate nehmen nach Zusatz von 5-Hydroxytryptamin oder Noradrenalin stark zu. Es wird daraus geschlossen, dass Nucleotidaggregate biogene Amine inkorporieren, wobei Nucleotid-Aminaggregate entstehen. Dies erklärt möglicherweise die Aufnahme und Speicherung von biogenen Aminen in nucleotidhaltigen subzellulären Organellen, z.B. von Blutplättchen, Nebennierenmark und noradrenergen Nerven.     

Changes in density of organelles fromNeurospora

Résumé Des mitochondries et des particules possédant certaines caractéristiques des peroxysomes ont été isolées duNeurospora crassa par centrifugation isopycnique. Lorsqu'elles sont extraites d'une culture réprimée, les mitochondries ont une densité apparente de 1,182 g×cm^–3, les particules peroxysomales, de 1,205 g×cm^–3. Isolées d'une culture complètement déréprimée, les densités respectives sont de 1,205 g×cm^–3 et de 1,219 g×cm^–3. La densité apparente des particules peroxysomales, mais non celle du stroma mitochondrial, est fortement affectée par des chocs hypotoniques ménagés.

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Supported by SNSF grant No. 3.575.71.     

Insights into NK cell biology from human genetics and disease associations

Rare human primary immunodeficiency disorders with extreme susceptibility to infections in infancy have provided important insights into immune function. Increasingly, however, primary immunodeficiencies are also recognized as a cause of other more common, often discrete, infectious susceptibilities. In a wider context, loss-of-function mutations in immune genes may also cause disorders of immune regulation and predispose to cancer. Here, we review the associations between human diseases and mutations in genetic elements affecting natural killer (NK) cell development and function. Although many such genetic aberrations significantly reduce NK cell numbers or severely impair NK cell responses, inferences regarding the role of NK cells in disease are confounded by the fact that most mutations also affect the development or function of other cell types. Still, data suggest an important role for NK cells in diseases ranging from classical immunodeficiency syndromes with susceptibility to viruses and other intracellular pathogens to cancer, autoimmunity, and hypersensitivity reactions.     

Insights into autotransplantation: the unexpected discovery of specific induction systems in bone marrow stromal cells

Many kinds of cells, including embryonic stem cells and tissue stem cells, have been considered candidates for transplantation therapy for neuro- and muscle-degenerative diseases. Bone marrow stromal cells (MSCs) also have great potential as therapeutic agents since they are easily isolated and can be expanded from patients without serious ethical or technical problems. Recently, new methods for the highly efficient and specific induction of functional neurons and skeletal muscle cells have been developed for MSCs. These induced cells were transplanted into animal models of stroke, Parkinson’s disease and muscle degeneration, resulting in the successful integration of transplanted cells and improvement in the behavior of the transplanted animals. Here I describe the discovery of these induction systems and focus on the potential use of MSC-derived cells for ‘auto-cell transplantation therapy’ in neuro- and muscle-degenerative diseases. Received 27 April 2006; received after revision 5 June 2006; accepted 22 August 2006     

Many mechanisms, one entrance: membrane protein translocation into the nucleus

The inner nuclear membrane harbors a unique set of membrane proteins, many of which interact with nuclear intermediate filaments and chromatin components and thus play an important role in nuclear organization and gene expression regulation. These membrane proteins have to be constantly transported into the nucleus from their sites of synthesis in the ER to match the growth of the nuclear membrane during interphase. Many mechanisms have evolved to enable translocation of these proteins to the nucleus. The full range of mechanisms goes from rare autophagy events to regulated translocation using the nuclear pore complexes. Though mechanisms involving nuclear pores are predominant, within this group an enormous mechanistic range is observed from free diffusion through the peripheral channels to many distinct mechanisms involving different nucleoporins and other components of the soluble protein transport machinery in the central channels. This review aims to provide a comprehensive insight into this mechanistic diversity.     

Sterols and sterol biosynthesis in the slugAplysia depilans

Zusammenfassung Aplysia depilans ist fähig, Lipide, einschliesslich der Sterinen, aus Azetat zu synthetisieren. Cholesterin ist das wichtigste Sterin (87%), aber auch andere Sterine, bisher bei Opisthobranchia unbekannt, wurden gefunden.