Intramembrane proteolysis by gamma-secretase

Gamma-secretase mediates the final proteolytic cleavage, which liberates amyloid beta-peptide (Abeta), the major component of senile plaques in the brains of Alzheimer disease patients. Therefore, gamma-secretase is a prime target for Abeta-lowering therapeutic strategies. gamma-Secretase is a protein complex composed of four different subunits, presenilin (PS), APH-1, nicastrin, and PEN-2, which are most likely present in a 1:1:1:1 stoichiometry. PS harbors the catalytically active site, which is critically required for the aspartyl protease activity of gamma-secretase. Moreover, numerous familial Alzheimer disease-associated mutations within the PSs increase the production of the aggregation-prone and neurotoxic 42-amino acid Abeta. Nicastrin may serve as a substrate receptor, although this has recently been challenged. PEN-2 is required to stabilize PS within the gamma-secretase complex. No particular function has so far been assigned to APH-1. The four components are sufficient and required for gamma-secretase activity. At least six different gamma-secretase complexes exist that are composed of different variants of PS and APH-1. All gamma-secretase complexes can exert pathological Abeta production. Assembly of the gamma-secretase complex occurs within the endoplasmic reticulum, and only fully assembled and functional gamma-secretase complexes are transported to the plasma membrane. Structural analysis by electron microscopy and chemical cross-linking reveals a water-containing cavity, which allows intramembrane proteolysis. Specific and highly sensitive gamma-secretase inhibitors have been developed; however, they interfere with the physiological function of gamma-secretase in Notch signaling and thus cause rather significant side effects in human trials. Modulators of gamma-secretase, which selectively affect the production of the pathological 42-amino acid Abeta, do not inhibit Notch signaling.     

Comparative analysis defines a broader FMRFamide-gated sodium channel family and determinants of neuropeptide sensitivity

FMRFamide (Phe-Met-Arg-Phe-amide, FMRFa) and similar neuropeptides are important physiological modulators in most invertebrates, but the molecular basis of FMRFa activity at its receptors is unknown. We therefore sought to identify the molecular determinants of FMRFa potency against one of its native targets, the excitatory FMRFa-gated sodium channel (FaNaC) from gastropod mollusks. Using molecular phylogenetics and electrophysiological measurement of neuropeptide activity, we identified a broad FaNaC family that includes mollusk and annelid channels gated by FMRFa, FVRIamides, and/or Wamides (or myoinhibitory peptides). A comparative analysis of this broader FaNaC family and other channels from the overarching degenerin (DEG)/epithelial sodium channel (ENaC) superfamily, incorporating mutagenesis and experimental dissection of channel function, identified a pocket of amino acid residues that determines activation of FaNaCs by neuropeptides. Although this pocket has diverged in distantly related DEG/ENaC channels that are activated by other ligands but enhanced by FMRFa, such as mammalian acid-sensing ion channels, we show that it nonetheless contains residues that determine enhancement of those channels by similar peptides. This study thus identifies amino acid residues that determine FMRFa neuropeptide activity at FaNaC receptor channels and illuminates the evolution of ligand recognition in one branch of the DEG/ENaC superfamily of ion channels.     

In vivo- undin vitro-verhalten temperatursensitiver mutanten des Tabakmosaikvirus

Summary It has been found that certain mutants of TMV with known amino acid exchanges produce abnormally low quantities of infectious virus particlesin vivo at 32°C, although the particles themselves are stable at even higher temperatures. A correlation between temperature sensitivity of the mutantsin vivo and the inability of their A-Proteins to reaggregate to rodsin vitro at 30°C is demonstrated. It is concluded that the amino acid exchanges in coat protein lead to temperature sensitivity of the mutants described.     

Hormonabhängige Enzymverteilung in Geweben

Zusammenfassung Es wurde gezeigt, daß sich männliche und weibliche Rattennieren durch die Verteilung und die Intensität ihrer alkalischen Phosphataseaktivität unterscheiden. Nach Kastration und nachfolgender östradiolbehandlung nimmt die Niere männlicher Ratten eine für weibliche Tiere typische Verteilung an.Mit 10 Textabbildungen     

Über die Hemmung der molybdänabhängigen Nitratreduktase durch Wolframat bei Neurospora crassa

Zusammenfassung Wolframat (als Na₂WO₄) erwies sich auch bei Neurospora crassa 3a6A als kompetitiver Antagonist für Molybdän; es inhibiert in 10⁵fach höherer Konzentration den Molybdäneffekt an der Nitratreduktase vollständig, in 10⁴fach höherer Konzentration um etwa 70%. Die 100fache Menge Wolfram ist ohne Einfluß auf den Funktionsablauf des Molybdäns an der Nitratreduktase von Neurospora crassa 3a6A.     

Die einjährigen Arten der GattungArnebia Forsk.

Zusammenfassung Die einjährigen Arten der GattungenArnebia werden, teilsJohnston, teilsPopov folgend, in die zwei UntergattungenArnebia undStrobila, letztere die SektionenStrobila undCornutae umfassend, gegliedert und die insgesamt 16 Arten, von denenA. johnstonii H.Riedl,A. waziristanica H.Riedl undA. simulatrix H.Riedl neu sind, ihrer Morphologie und systematischen Stellung nach besprochen.Durchgeführt mit Unterstützung durch National Science Foundation Grant G 16325.Die Zeichnungen wurden von FrauErika Kubelka ausgeführt, wofür ihr auch an dieser Stelle aufrichtigster Dank gesagt sei.     

Experimente zur analyse der choanenentstehung und formbildung der nase bei triturus

Ohne ZusammenfassungHerrn Professor Dr. O.Mangold zum 70. Geburtstag in Dankbarkeit und Verehrung gewidmet.Mit dankenswerter Unterstützung derDeutschen Forschungsgemeinschaft.