- Alpha sheet
The alpha sheet (also known as an alpha pleated sheet or a polar pleated sheet) is a hypothetical
secondary structurein proteins, first proposed by Linus Paulingand Robert Coreyin 1951.Pauling, L. & Corey, R. B. (1951). The pleated sheet, a new layer configuration of polypeptide chains. "Proc. Natl. Acad. Sci. USA" 37, 251–6. PMID 14834147] Pauling, L. & Corey, R. B. (1951). The structure of feather rachis keratin. "Proc. Natl. Acad. Sci. USA" 37, 256–261. PMID 14834148] Pauling, L. & Corey, R. B. (1951). Configurations of Polypeptide Chains With Favored Orientations Around Single Bonds: Two New Pleated Sheets. "Proc. Natl. Acad. Sci. USA" 37, 729–740. PMID 16578412] The hydrogen bonding pattern in an alpha sheet is similar to that of a beta sheet, but the orientation of the carbonyland aminogroups in the peptide bondunits is distinctive; in a single "alpha strand", all of the carbonyl groups are oriented in the same direction on one side of the pleat, and all of the amino groups are oriented in the same direction on the opposite side of the sheet. Thus the alpha sheet accumulates an inherent separation of electrostatic charge, with one edge of the sheet exposing negatively charged carbonyl groups and the opposite edge exposing positively charged amino groups. Unlike the alpha helixand beta sheet, the alpha sheet configuration does not require all component amino acidresidues to lie within a single region of dihedral angles; instead, the alpha sheet contains residues of alternating dihedrals in the traditional right-handed (αR) and left-handed (αL) helical regions of Ramachandran space. Although the alpha sheet is only very rarely observed in natural protein structures,Daggett V. (2006). Alpha-sheet: The toxic conformer in amyloid diseases? "Acc Chem Res" 39(9):594-602. PMID 16981675 ] it is a stable form accessible to amyloidogenic proteins in molecular dynamicssimulations.Armen RS, DeMarco ML, Alonso DO, Daggett V. (2004). Pauling and Corey's alpha-pleated sheet structure may define the prefibrillar amyloidogenic intermediate in amyloid disease. "Proc Natl Acad Sci USA" 101(32):11622-7. PMID 15280548] Alpha sheets have also been observed in X-ray crystallographystructures of designed peptides.
When Pauling and Corey first proposed the alpha sheet, they suggested that it agreed well with
fiber diffractionresults from beta-keratinfibers. However, since the alpha sheet did not appear to be energetically favorable, they argued that beta sheets would more common in normal proteins, and subsequent demonstration that beta-keratin is made of beta sheets consigned the alpha sheet proposal to obscurity. Recently the alpha strand conformation has been observed in isolated instances in native stateproteins as solved by X-ray crystallographyor protein NMR, although an extended alpha sheet was not identified in any known natural protein. Native proteins identified as containing alpha-strand regions or alpha-sheet-patterned hydrogen bonding include synaptotagmin, lysozyme, and potassium channels, where the alpha-strands line the ion-conducting pore.
Alpha-sheet conformations have been observed in crystal structures of short non-natural peptides, especially those containing a mixture of L and D
amino acids. The first crystal structure containing an alpha sheet was observed in the capped tripeptide Boc–AlaL–a-IleD–IleL–OMe.Di Blasio B, Saviano M, Fattorusso R, Lombardi A, Pedone C, Valle V, Lorenzi GP. (1994). A crystal structure with features of an antiparallel alpha-pleated sheet. "Biopolymers" 34(11):1463-8. PMID 7827259 ] Other peptides that assume alpha-sheet structures include capped di phenyl- glycine-based dipeptidesDe Simone G, Lombardi A, Galdiero S, Nastri F, Di Costanzo L, Gohda S, Sano A, Yamada T, Pavone V. (2000). The crystal structure of a Dcp-containing peptide. "Biopolymers" 53(2):182-8. PMID 10679622 ] and tripeptides.Pavone V, Lombardi A, Saviano M, Nastri F, Zaccaro L, Maglio O, Pedone C, Omote Y, Yamanaka Y, Yamada T. (1998). Conformational behaviour of C(alpha,alpha)-diphenylglycine: folded vs. extended structures in DphiG-containing tripeptides. 4(1):21-32. PMID 9523753]
Role in amyloidogenesis
The alpha sheet has been proposed as a possible intermediate state in the
conformational changein the formation of amyloidfibrils by peptides and proteins such as amyloid beta, poly- glutaminerepeats, lysozyme, prionproteins, and transthyretinrepeats, all of which are associated with protein misfolding disease. For example, amyloid beta is a major component of amyloid plaques in the brains of Alzheimer's diseasepatients, and polyglutamine repeats in the huntingtin proteinare associated with Huntington's disease.Armen RS, Bernard BM, Day R, Alonso DO, Daggett V. (2005). Characterization of a possible amyloidogenic precursor in glutamine-repeat neurodegenerative diseases. "Proc Natl Acad Sci USA" 102(38):13433-8. PMID 16157882] These proteins undergo a conformational changefrom largely random coilor alpha helixstructures to the highly ordered beta sheetstructures found in amyloid fibrils. Most beta sheets in known proteins are "twisted" about 15° for optimal hydrogen bonding and stericpacking; however, some evidence from electron crystallographysuggests that at least some amyloid fibrils contain "flat" sheets with only 1-2.5° of twist. Jimenez, J. L., Nettleton, E. J., Bouchard, M., Robinson, C. V., Dobson, C. M. & Saibil, H. R. (2002). The protofilament structure of insulin amyloid fibrils. "Proc. Natl. Acad. Sci. USA" 99, 9196–9201. PMID 12093917] An alpha-sheet amyloid intermediate is suggested to explain some anomalous features of the amyloid fibrillization process, such as the evident amino acid sequencedependence of amyloidogenesis despite the belief that the amyloid fold is mainly stabilized by the protein backboneand the acceleration of fibrillization in the presence of a magnetic field.Fraser, P. E., Duffy, L. K., O'Mally, M. B., Nguyen, J., Inouye, H. & Kirschner, D. A. (1991). Morphology and antibody recognition of synthetic beta-amyloid peptides. J. Neurosci. Res. 28, 474–485. PMID 1908024.] Malinchik, S. B., Inouye, H., Szumowski, K. E. & Kirschner, D. A. (1998). Structural analysis of Alzheimer's beta(1-40) amyloid: protofilament assembly of tubular fibrils. "Biophys. J." 74, 537–545. PMID 9449354]
Xu Xu S. Aggregation drives "misfolding" in protein amyloid fiber formation. "Amyloid" 2007 Jun;14(2):119-31. PMID 17577685] , using atomic force microscopy, has shown that formation of amyloid fibers is a two-step process in which proteins first aggregate into colloidal spheres of ~20nm diameter. The spheres then join together spontaneously to form linear chains, which evolve into mature amyloid fibers. The formation of these linear chains appears to be driven by the development of an electrostatic dipole in each of the colloidal spheres strong enough to overcome coulomb repulsion. This suggests a possible mechanism by which alpha sheet may promote amyloid aggregation; the peptide bond has a relatively large intrinsic electrostatic dipole, but normally the dipoles of nearby bonds cancel each other out. In the alpha sheet, unlike other conformations, the peptide bonds are oriented in parallel so that the dipoles of the individual bonds can add up to create a strong overall electrostatic dipole.
Notably, the protein
lysozymeis among the few native-state proteins shown to contain an alpha-strand region; lysozyme from both chickens and humans contains an alpha strand located close to the site of a mutationknown to cause hereditary amyloidosisin humans, usually an autosomal dominantgenetic disease. Molecular dynamics simulations of the mutant protein reveal that the region around the mutation assumes an alpha strand conformation.Armen, R. S.; DeMarco, M. L.; Alonso, D. O. V.; Daggett, V. (2004). Pauling and Corey’s R-pleated sheet structure may define the prefibrillar amyloidogenic intermediate in amyloid disease. "Proc. Natl. Acad. Sci. USA" 101: 11622-11627. PMID 15280548] Lysozyme is among the naturally occurring proteins known to form amyloid fibers under experimental conditions, and both natively alpha-strand region and the mutation site fall within the larger region identified as the core of lysozyme amyloid fibrillogenesis.Frare, D.; Polverino de Laureto, P.; Zurdo, J.; Dobson, C. M., Fontana, A. (2004). A highly amyloidogenic region of hen lysozyme. "J Mol Biol" 340: 1153-1165. PMID 15236974 ] Frare E, Mossuto MF, Polverino de Laureto P, Dumoulin M, Dobson CM, Fontana A. (2006). Identification of the core structure of lysozyme amyloid fibrils by proteolysis. "J Mol Biol" 361(3):551-61. PMID 16859705]
A mechanism for direct alpha sheet and beta sheet interconversion has also been suggested, based on
peptide plane flippingin which the αRαL dipeptide inverts to produce a ββ dihedral angle conformation. This process has also been observed in simulations of transthyretinMilner-White JE, Watson JD, Qi G, Hayward S. (2006). Peptide plane can flip in two opposite directions: implication in amyloid formation of transthyretin. "J Phys Chem B" 110(12):5829-33. PMID 16553385 ] and implicated as occurring naturally in certain protein families by examination of their dihedral angle conformations in crystal structures.Milner-White JE, Watson JD, Qi G, Hayward S. (2006). Amyloid formation may involve alpha- to beta sheet interconversion via peptide plane flipping. "Structure" 14(9):1369-76. PMID 16962968]
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