Structure of the cross-beta spine of amyloid-like fibrils

Numerous soluble proteins convert to insoluble amyloid-like fibrils that have common properties. Amyloid fibrils are associated with fatal diseases such as Alzheimer's, and amyloid-like fibrils can be formed in vitro. For the yeast protein Sup35, conversion to amyloid-like fibrils is associated with a transmissible infection akin to that caused by mammalian prions. A seven-residue peptide segment from Sup35 forms amyloid-like fibrils and closely related microcrystals, from which we have determined the atomic structure of the cross-beta spine. It is a double beta-sheet, with each sheet formed from parallel segments stacked in register. Side chains protruding from the two sheets form a dry, tightly self-complementing steric zipper, bonding the sheets. Within each sheet, every segment is bound to its two neighbouring segments through stacks of both backbone and side-chain hydrogen bonds. The structure illuminates the stability of amyloid fibrils, their self-seeding characteristic and their tendency to form polymorphic structures.     

Amyloid-like fibrils of ribonuclease A with three-dimensional domain-swapped and native-like structure

Amyloid or amyloid-like fibrils are elongated, insoluble protein aggregates, formed in vivo in association with neurodegenerative diseases or in vitro from soluble native proteins, respectively. The underlying structure of the fibrillar or 'cross-beta' state has presented long-standing, fundamental puzzles of protein structure. These include whether fibril-forming proteins have two structurally distinct stable states, native and fibrillar, and whether all or only part of the native protein refolds as it converts to the fibrillar state. Here we show that a designed amyloid-like fibril of the well-characterized enzyme RNase A contains native-like molecules capable of enzymatic activity. In addition, these functional molecular units are formed from a core RNase A domain and a swapped complementary domain. These findings are consistent with the zipper-spine model in which a cross-beta spine is decorated with three-dimensional domain-swapped functional units, retaining native-like structure.     

低碳锰钢中周期性带状组织

用扫描电镜和电子探针研究了低碳锰钢中的周期性带状组织，结果表明，在全部研究用钢中，钢锭经热轧后均出现这种组织，其严重程度随钢的成分而异，并随坯带加工顺序而增加，带状组织与锰的显微偏析等因素有关，适当的调整碳锰以及形成模跨铁素体带的转变产物可降低带状组织的严重程度。     

Atomic structures of amyloid cross-beta spines reveal varied steric zippers

Amyloid fibrils formed from different proteins, each associated with a particular disease, contain a common cross-beta spine. The atomic architecture of a spine, from the fibril-forming segment GNNQQNY of the yeast prion protein Sup35, was recently revealed by X-ray microcrystallography. It is a pair of beta-sheets, with the facing side chains of the two sheets interdigitated in a dry 'steric zipper'. Here we report some 30 other segments from fibril-forming proteins that form amyloid-like fibrils, microcrystals, or usually both. These include segments from the Alzheimer's amyloid-beta and tau proteins, the PrP prion protein, insulin, islet amyloid polypeptide (IAPP), lysozyme, myoglobin, alpha-synuclein and beta(2)-microglobulin, suggesting that common structural features are shared by amyloid diseases at the molecular level. Structures of 13 of these microcrystals all reveal steric zippers, but with variations that expand the range of atomic architectures for amyloid-like fibrils and offer an atomic-level hypothesis for the basis of prion strains.     

The influence of magnesium and calcium ions on the force produced in rigor muscle

Zusammenfassung Die Rigorspannung glycerinextrahierter Skeletmuskelfasern (Caiman crocodilus) und fibrillärer Insektenflugmuskelfasern (DLM) (L. maximus) konnte durch Zugabe von zweiwertigen Kationen und pH-Erniedrigung reversibel erniedrigt werden sowie durch pH-Erhöhung und Zugabe von Sulfationen erhöht werden. Da unter ähnlichen Bedingungen im Rigor Veränderungen des Abstandes von Aktin- und Myosinfilamenten nachgewiesen wurden^4,5, wurden die beobachteten Spannungsänderungen im Rigor auf Grund neuerer Crossbridgemodelle^3,9 diskutiert.

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We are grateful to Prof. Dr.J. C. Rüegg for helpful suggestions.

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Supported by Deutsche Forschungsgemeinschaft, Grant No. Ru 154/7.     

Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice

Gliomas are the most common primary malignant brain tumours and are classified into four clinical grades, with the most aggressive tumours being grade 4 astrocytomas (also known as glioblastoma multiforme; GBM). Frequent genetic alterations in GBMs (refs 2-5) result in stimulation of common signal transduction pathways involving Ras, Akt and other proteins. It is not known which of these pathways, if any, are sufficient to induce GBM formation. Here we transfer, in a tissue-specific manner, genes encoding activated forms of Ras and Akt to astrocytes and neural progenitors in mice. We found that although neither activated Ras nor Akt alone is sufficient to induce GBM formation, the combination of activated Ras and Akt induces high-grade gliomas with the histological features of human GBMs. These tumours appear to arise after gene transfer to neural progenitors, but not after transfer to differentiated astrocytes. Increased activity of RAS is found in many human GBMs (ref. 11), and we show here that Akt activity is increased in most of these tumours, implying that combined activation of these two pathways accurately models the biology of this disease.