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30]][“Agonist P”

Only the prion protein appears to be capable of transmitting disease.Still, there are striking parallels in the physicochemical properties of these three diverse polypeptides.Many detailed biophysical studies have been published, using both chemically synthesized peptides and recombinant proteins.In this brief review, we discuss recent efforts to de ne the kinetics of conversion of monomer to aggregate, and to discover Aniracetam compounds capable of interfering with polypeptide aggregation.Such compounds may serve as leads in the effort to develop effective therapies against these devastating neurodegenerative diseases.These algorithms were developed for globular soluble proteins, and their extension to the three polypeptides of interest here is problematic.With this caveat in mind, we report on the consensus sequence.PrP is predicted to contain an interior helix followed by a short strand.The huntingtin fragment is predicted to be primarily helical.Based on these three peptide sequences, there is no consistent predicted propensity towards sheet, and hence, no support for the hypothesis.A general feature is the conformational exibility or Calcitriol adaptability of these polypeptides.In fact, proteins unrelated to known disease states can be induced to form amyloid brils by reducing the conformational stability of the folded globular protein. Perhaps a modi ed version of the hypothesis is more globally applicable; specically, proteins and peptides prone to amyloid bril formation are those that have a domain that readily adopts multiple conformations.This analysis may be somewhat misleading; polyglutamine may act like a much more hydrophobic group due to strong hydrogen bonding between the polypeptide backbone and side chain amides.The distribution of hydrophobic side chains likely plays a signicant role as well.It is possible to generate libraries of synthetic peptides of alternating polar and nonpolar residues that have a strong predilection towards selfassociating into amyloidlike aggregates. A A undergoes substantial conformational shifts depending on its environment and can easily convert among disordered, helical, and sheet conformers as solution conditions change.Under membranemimicking conditions, A contains a signi cant amount of helical character. In physiological buffers, both random coil and sheet secondary structure are observed, with the sheet content increasing dramatically with peptide concentration. This indicates that the sheetcontaining conformers are oligomeric.A conformation is both pH and saltsensitive, with an increase in sheet content in the presence of salt and in slightly acidic conditions.His residues at positions and likely contribute to the pH effect on the stability of aggregates, while the increase in sheet with salt likely derives from the peptide s hydrophobic regions. NMR solution studies on A indicated that the soluble monomer in water lacks regular secondary structural features. Rather, the peptide adopts a metastable collapsed coil structure around the central hydrophobic region. The picture that emerges is of a peptide that adopts a helical structure when anchored in its natural membrane environment, that undergoes hydrophobicdriven collapse into a monomer lacking regular secondary structural features when released from the membrane by proteolysis, and that subsequently simultaneously oligomerizes and forms an extended sheet.Removal of the single disul de bond substantially reduces the stability of the helical monomer. Based on circular dichroism studies, polyglutamines are strong sheet formers, retaining a sheet structure even in the helicalpromoting solvent triuoroethanol.

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