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Lucke C.,Max Planck Research Unit for Enzymology of Protein Folding | Weiwad M.,Max Planck Research Unit for Enzymology of Protein Folding
Current Medicinal Chemistry | Year: 2011

The immunophilins are proteins which are capable of influencing the immune response in combination with an immunosuppressive drug. Their natural function, however, is mainly the cis/trans isomerization of peptidyl-prolyl bonds in other proteins. This review lists all immunophilin structure coordinates currently available in the RCSB protein data bank and highlights the key active-site factors that define their catalytic and immunological action. In addition, an overview of biologically-relevant functions is provided for various immunophilin members. © 2011 Bentham Science Publishers.


Scheidt H.A.,University of Leipzig | Scheidt H.A.,Martin Luther University of Halle Wittenberg | Morgado I.,Martin Luther University of Halle Wittenberg | Rothemund S.,The Interdisciplinary Center | And 2 more authors.
Angewandte Chemie - International Edition | Year: 2011

The secondary structure elements in Aβ protofibrils (see TEM image) were determined at a single residue level by solid-state NMR spectroscopy. The β-sheet elements of the mature fibrils are already preformed in protofibrils, but these regions have to elongate during the conversion into mature fibrils. The data have important implications for understanding the process of fibril formation in general as well as the structural basis of Alzheimer's disease. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Hirsch I.,Max Planck Research Unit for Enzymology of Protein Folding | Weiwad M.,Max Planck Research Unit for Enzymology of Protein Folding | Prell E.,Max Planck Research Unit for Enzymology of Protein Folding | Ferrari D.M.,Max Planck Research Unit for Enzymology of Protein Folding
Apoptosis | Year: 2014

Endoplasmic reticulum protein 29 (ERp29) belongs to the redox-inactive PDI-Dβ-subfamily of PDI-proteins. ERp29 is expressed in all mammalian tissues examined. Especially high levels of expression were observed in secretory tissues and in some tumors. However, the biological role of ERp29 remains unclear. In the present study we show, by using thyrocytes and primary dermal fibroblasts from adult ERp29-/- mice, that ERp29 deficiency affects the activation of the ATF6-CHOP-branch of unfolded protein response (UPR) without influencing the function of other UPR branches, like the ATF4-eIF2α-XBP1 signaling pathway. As a result of impaired ATF6 activation, dermal fibroblasts and adult thyrocytes from ERp29-/- mice display significantly lower apoptosis sensitivities when treated with tunicamycin and hydrogen peroxide. However, in contrast to previous reports, we could demonstrate that ERp29 deficiency does not alter thyroglobulin expression levels. Therefore, our study suggests that ERp29 acts as an escort factor for ATF6 and promotes its transport from ER to Golgi apparatus under ER stress conditions. © 2013 Springer Science+Business Media New York.


Schiene-Fischer C.,Max Planck Research Unit for Enzymology of Protein Folding | Aumeuller T.,Max Planck Research Unit for Enzymology of Protein Folding | Fischer G.,Max Planck Research Unit for Enzymology of Protein Folding
Topics in Current Chemistry | Year: 2013

Peptide bond cis/trans isomerases (PCTIases) catalyze an intrinsically slow rotational motion taking part in the conformational dynamics of a protein backbone in all of its folding states. In this way, PCTIases assist other proteins to shape their functionally active structure. They have been associated with viral, bacterial, and parasitic infection, signal transduction, cell differentiation, altered metabolic activity, apoptosis, and many other physiological and pathophysiological processes. The need to understand, characterize, and control biochemical steps which contribute to the folding of proteins is a problem being addressed in many laboratories today. This review discusses the biochemical basis that the peptidyl prolyl cis/trans isomerase (PPIase) family of PCTIases uses for the control of bioactivity. Special emphasis is given to recent developments in the field of biocatalytic features of PPIases, the mechanism of catalysis, and enzyme inhibition. © Springer-Verlag Berlin Heidelberg 2011.


Fandrich M.,Max Planck Research Unit for Enzymology of Protein Folding
Acta neuropathologica communications | Year: 2014

INTRODUCTION: The self-assembly of Aβ peptides into a range of conformationally heterogeneous amyloid states represents a fundamental event in Alzheimer's disease. Within these structures oligomeric intermediates are considered to be particularly pathogenic. To test this hypothesis we have used a conformational targeting approach where particular conformational states, such as oligomers or fibrils, are recognized in vivo by state-specific antibody fragments.RESULTS: We show that oligomer targeting with the KW1 antibody fragment, but not fibril targeting with the B10 antibody fragment, affects toxicity in Aβ-expressing Drosophila melanogaster. The effect of KW1 is observed to occur selectively with flies expressing Aβ(1-40) and not with those expressing Aβ(1-42) or the arctic variant of Aβ(1-42) This finding is consistent with the binding preference of KW1 for Aβ(1-40) oligomers that has been established in vitro. Strikingly, and in contrast to the previously demonstrated in vitro ability of this antibody fragment to block oligomeric toxicity in long-term potentiation measurements, KW1 promotes toxicity in the flies rather than preventing it. This result shows the crucial importance of the environment in determining the influence of antibody binding on the nature and consequences of the protein misfolding and aggregation.CONCLUSIONS: While our data support to the pathological relevance of oligomers, they highlight the issues to be addressed when developing inhibitory strategies that aim to neutralize these states by means of antagonistic binding agents.


Garvey M.,Max Planck Research Unit for Enzymology of Protein Folding | Garvey M.,RWTH Aachen | Morgado I.,Max Planck Research Unit for Enzymology of Protein Folding
Biochemical and Biophysical Research Communications | Year: 2013

The kinetic mechanism of amyloid aggregation remains to be fully understood. Investigations into the species present in the different kinetic phases can assist our comprehension of amyloid diseases and further our understanding of the mechanism behind amyloid β (Aβ) (1-40) peptide aggregation. Thioflavin T (ThT) fluorescence and transmission electron microscopy (TEM) have been used in combination to monitor Aβ(1-40) aggregation in vitro at both normal and higher than standard concentrations. The observed fibrillation behaviour deviates, in several respects, from standard concepts of the nucleation-polymerisation models and shows such features as concentration-dependent non-linear effects in the assembly mechanism. Aβ(1-40) fibrillation kinetics do not always follow conventional kinetic mechanisms and, specifically at high concentrations, intermediate structures become populated and secondary processes may further modify the fibrillation mechanism. © 2013 Elsevier Inc.


Erdmann F.,Max Planck Research Unit for Enzymology of Protein Folding | Zhang Y.,TU Dresden
Molecular BioSystems | Year: 2010

Using light to tune the activity of proteins represents a very attractive avenue for creating various temporal interferences in living systems. In this mini-review, we highlight a few recent developments in this broad and exciting field. Among the various methods, we have discussed in more detail the advantages and future challenges in using light switchable drugs to regulate the signaling proteins in the immune system. © 2010 The Royal Society of Chemistry.


Huang Y.,Max Planck Research Unit for Enzymology of Protein Folding | Jahreis G.,Max Planck Research Unit for Enzymology of Protein Folding | Lucke C.,Max Planck Research Unit for Enzymology of Protein Folding | Wildemann D.,Max Planck Research Unit for Enzymology of Protein Folding | Fischer G.,Max Planck Research Unit for Enzymology of Protein Folding
Journal of the American Chemical Society | Year: 2010

Photocontrol of the backbone conformation is a useful step forward in regulating the bioactivities of peptides and proteins by means of external signals. In the present work, the selenium analogue of a peptide bond was introduced into tetrapeptides to obtain surprisingly stable selenoxo peptides. Selenoxo peptide bonds allow for a marked increase of cis content in the photostationary state of peptide chains when irradiated with UV light near 290 nm. Slow thermal re-equilibration with rate constants between 9.9 × 10-4 and 1.3 × 10-5 s-1 shows that the transient nonequilibrium conformations exist long enough to monitor the isomer specificity of biochemical reactions. © 2010 American Chemical Society.


Huang Y.,Max Planck Research Unit for Enzymology of Protein Folding | Jahreis G.,Max Planck Research Unit for Enzymology of Protein Folding | Fischer G.,Max Planck Research Unit for Enzymology of Protein Folding | Lucke C.,Max Planck Research Unit for Enzymology of Protein Folding
Chemistry - A European Journal | Year: 2012

The amide bond as peptide linkage plays an important role in protein structure and function. A large number of theoretical and experimental studies have focused on the specific nature of the peptide bond. Little attention, however, has been paid to their chalcogen-substituted congeners, although experimental data on thioamides revealed inconsistencies with the conventional view of amide resonance theory. Here, we employed thioxo and selenoxo substitution to determine experimentally how heavier chalcogens affect the properties of the peptide bond and adjacent atoms. NMR data revealed pronounced deshielding of heteronuclei within a three-bond distance to the chalcogen atom; this indicates an enhanced electron-withdrawing potential of the heavier chalcogens despite their lower electronegativities compared to oxygen. Interestingly, linear correlations were observed between chalcogen atomic polarizability and the chemical shift values of those neighboring heteronuclei as well as several physicochemical properties, such as electronic excitation energy, C-N rotation barrier, dipole moment and amide proton dissociation. We conclude that the chalcogen polarizability, which relates to the charge capacity, is the dominant factor that determines the electronic properties of peptide bonds substituted with heavier chalcogens. Chalcogen polarizability makes the difference! Replacement of oxygen in a peptide bond by either sulfur or selenium has a considerable impact on the electronic structure and physicochemical properties of this amide moiety. Both in thioxo and selenoxo peptides, the nuclear shielding, electronic excitation energy, cis/trans rotation barrier and amide pKa value show direct correlation to the atomic polarizability of the chalcogen. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Thiele A.,Max Planck Research Unit for Enzymology of Protein Folding
Methods in molecular biology (Clifton, N.J.) | Year: 2010

Protein function is highly regulated in pathways that are responsible for complex biochemical mechanisms such as growth, metabolism, and signal transduction. One of the most important mechanisms is posttranslational modification (PTM) changing protein surfaces by phosphorylation, sulfation, acetylation, methylation, glycosylation, and sumoylation resulting in a more than 100-fold higher complexity (Geiss-Friedlander and Melchior, Nat Rev Mol Cell Biol 8, 947-956, 2007; Hunter, Mol Cell 28, 730-738, 2007). This chapter presents a very efficient way to detect potential phosphorylation sites in protein families using overlapping peptides covering the complete primary structures (peptide scans) immobilized on glass slides. Results of kinase activity fingerprinting of cell lysates using peptide microarrays displaying peptide scans through all human peptidyl-prolyl-cis/trans-isomerases are shown.

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