Lithostathine Quadruple-helical Filaments Form Proteinase K-resistant Deposits in Creutzfeldt-Jakob Disease

Abstract

Autocatalytic cleavage of lithostathine leads to the formation of quadruple-helical fibrils (QHF-litho) that are present in Alzheimer's disease. Here we show that such fibrils also occur in Creutzfeldt-Jakob and Gerstmann-Strä ussler-Scheinker diseases, where they form protease-K-resistant deposits and co-localize with amyloid plaques formed from prion protein. Lithostathine does not appear to change its native-like, globular structure during fibril formation. However, we obtained evidence that a cluster of six conserved tryptophans, positioned around a surface loop, could act as a mobile structural element that can be swapped between adjacent protein molecules, thereby enabling the formation of higher order fibril bundles. Despite their association with these clinical amyloid deposits, QHF-litho differ from typical amyloid fibrils in several ways, for example they produce a different infrared spectrum and cannot bind Congo Red, suggesting that they may not represent amyloid structures themselves. Instead, we suggest that lithostathine constitutes a novel component decorating disease-associated amyloid fibrils. Interestingly, [6,6 ]bibenzothiazolyl-2,2 -diamine, an agent found previously to disrupt aggregates of huntingtin associated with Huntington's disease, can dissociate lithostathine bundles into individual protofilaments. Disrupting QHF-litho fibrils could therefore represent a novel therapeutic strategy to combat clinical amyloidoses.

High-speed atomic force microscopy coming of age

“…protease-K-resistant fibrils [181] that deposit in the brain of patients with Creutzfeld-Jakob disease [182] and Gertsmann-Straüssler-Scheinker syndrome [183], especially during the very early stages. figure 14) and (2) fusion of a growing protofibril to a pre-existing profofibril (light-blue arrows in figure 14).…”

Aggregation of the Acylphosphatase from Sulfolobus solfataricus

“…On the one hand, amyloid formation may occur readily from peptides as short as 5 residues, where formation of structure before assembly is rather unlikely given the short length of the peptides (12). On the other hand, a number of observations have indicated that fibrillar aggregates may originate from the assembly of globular protein molecules in their native or native-like state (13,14). The yeast prion Ure2p was shown to form fibrils that display birefringence upon Congo red binding and increased resistance to proteinase K treatment, typical of amyloid fibrils (15)(16)(17).…”

“…Accordingly, x-ray fiber diffraction analysis has shown that the fibrils do not possess a cross-␤-structure (18). Similarly, lithostathine, a protein that forms both independent and colocalized deposits with amyloid ␤ plaques, neurofibrillary tangles, and PrP sc plaques, maintains its native content of secondary structure, although it aggregates into fibrillar structures (14). In this case the resulting proteinase K-resistant fibrils do not bind Congo red in addition to showing no cross-␤-structure (14).…”

“…Similarly, lithostathine, a protein that forms both independent and colocalized deposits with amyloid ␤ plaques, neurofibrillary tangles, and PrP sc plaques, maintains its native content of secondary structure, although it aggregates into fibrillar structures (14). In this case the resulting proteinase K-resistant fibrils do not bind Congo red in addition to showing no cross-␤-structure (14). The ability of these two proteins to form fibrillar structures under non-denaturing conditions close to a physiological medium suggests that a substantial unfolding is not required (13,14).…”

PAP IB, a new member of the Reg gene family: Cloning, expression, structural properties, and evolution by gene duplication

“…They have been described as inhibitors of calcium carbonate crystal growth in vitro ( [1] and [2]), as growth factors ( [3] and [4]), as mitogens for pancreatic β-cells ( [5] and [6]), and as a motoneuron neurotrophic factor [7]. They have also been implicated in carcinogenesis ( [8]; [9] and [10]), in the improvement of diabetes in murine models ( [11] and [12]), and in neurodegenerative diseases ( [13] and [14]). …”