Alpha Sheet

Alpha sheet (also known as alpha pleated sheet or polar pleated sheet) is an atypical secondary structure in proteins, first proposed by Linus Pauling and Robert Corey in 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. Pauling, L. & Corey, R. B. (1951). The structure of feather rachis keratin. ''Proc. Natl. Acad. Sci. USA'' 37, 256–261. 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. The hydrogen bonding pattern in an alpha sheet is similar to that of a beta sheet, but the orientation of the carbonyl and amino groups in the peptide bond units is distinctive; in a single strand, all the carbonyl groups are oriented in the same direction on one side of the pleat, and all 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 helix and beta sheet, the alpha sheet configuration does not require all component amino acid residues to lie within a single region of dihedral angles; instead, the alpha sheet contains residues of alternating dihedrals in the traditional right-handed (α_R) and left-handed (α_L) helical regions of Ramachandran space. Although the alpha sheet is only rarely observed in natural protein structures, it has been speculated to play a role in amyloid disease Daggett V. (2006). Alpha-sheet: The toxic conformer in amyloid diseases? ''Acc Chem Res'' 39(9):594-602. and it was found to be a stable form for amyloidogenic proteins in molecular dynamics simulations.Babin V, Roland C, Sagui C. (2011). The alpha-sheet: A missing in action secondary structure. ''Proteins'' 79:937-946. Armen RS, DeMarco ML, Alonso DO, Daggett V. (2011). 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. Alpha sheets have also been observed in X-ray crystallography structures of designed peptides.

The regular formation of alpha-sheet by unfolded proteins inevitably involves many L amino acid residues readily adopting the alphaL conformation, which appears at first sight to go against textbook chemistry, which is that, of the 20 amino acids, it is glycine that strongly favours this conformation. The conundrum is resolved by realizing that the alphaL region comprises two overlapping areas, here called γL and αL, which should be considered separately. It turns out that, while the γL conformation is adopted, almost exclusively, by glycine, the αL conformation of alpha-sheet is more commonly, or about as commonly, adopted by any of 15 L-amino acids compared to glycine, the exceptions being proline, threonine, valine and isoleucine, which are rare at this conformation.Hayward S. (2021). Determination of amino acids that favour the alphaL region using Ramachandran propensity plots. Implications for alpha-sheet as the possible amyloid intermediate. ''Journal of Structural Biology'' 213:α107738. Hence, of the 20 amino acids, 16 readily adopt the αL conformation.

Experimental evidence

When Pauling and Corey first proposed the alpha sheet, they suggested that it agreed well with fiber diffraction results from beta-keratin fibers. However, since the alpha sheet did not appear to be energetically favorable, they argued that beta sheets would occur more commonly among normal proteins, and subsequent demonstration that beta-keratin is made of beta sheets consigned the alpha sheet proposal to obscurity. However the alpha strand conformation is observed in isolated instances in native state proteins as solved by X-ray crystallography or protein NMR, although an extended alpha sheet is not identified in any known natural protein. Native proteins 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.

Evidence for the existence of alpha-sheet in a mutant form of transthyretin has been presented.Hilaire MR, Ding B, Mukherjee D, Chen J, Gai F. (2018). Possible existence of alpha-sheets in the amyloid fibrils formed by a mutant form of a peptide from transthyretin. ''Journal of the American Chemical Society '' 140:629-635. 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–Ala_L– a-Ile_D–Ile_L– O Me.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. Other peptides that assume alpha-sheet structures include capped diphenyl-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. 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.

Role in amyloidogenesis

The alpha sheet has been proposed as a possible intermediate state in the conformational change in the formation of amyloid fibrils by peptides and proteins such as amyloid beta, poly-glutamine repeats, lysozyme, prion proteins, and transthyretin repeats, 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 disease patients, and polyglutamine repeats in the huntingtin protein are 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. These proteins undergo a conformational change from largely random coil or alpha helix structures to the highly ordered beta sheet structures found in amyloid fibrils. Most beta sheets in known proteins are "twisted" about 15° for optimal hydrogen bonding and steric packing; however, some evidence from electron crystallography suggests 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. An alpha-sheet amyloid intermediate is suggested to explain some anomalous features of the amyloid fibrillization process, such as the evident amino acid sequence dependence of amyloidogenesis despite the belief that the amyloid fold is mainly stabilized by the protein backbone.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. .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.

Xu,Xu S. Aggregation drives "misfolding" in protein amyloid fiber formation. ''Amyloid'' 2007 Jun;14(2):119-31. 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 ≈20 nm 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 lysozyme is 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 mutation known to cause hereditary amyloidosis in humans, usually an autosomal dominant genetic disease. Molecular dynamics simulations of the mutant protein reveal that the region around the mutation assumes an alpha strand conformation. 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. 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.

A mechanism for direct alpha sheet and beta sheet interconversion has also been suggested, based on peptide plane flipping in which the α_Rα_L dipeptide inverts to produce a ββ dihedral angle conformation. This process has also been observed in simulations of transthyretinYang MF, Lei M, Yordanov B, Huo SH. (2006). Peptide plane can flip in two opposite directions: implication in amyloid formation of transthyretin. ''J Phys Chem B'' 110(12):5829-33. and implicated as occurring naturally in certain protein families by examination of their dihedral angle conformations in crystal structures.Milner-White EJ, 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. Hayward S, Milner-White EJ. (2008). The geometry of alpha-sheet: Implications for its possible function as amyloid precursor in proteins ''Proteins'' 71:425-431. It is suggested that alpha-sheet folds into multi-strand solenoids.Hayward S, Milner-White EJ. (2011). Simulation of the β- to α-sheet transition results in a twisted sheet for antiparallel and an α-nanotube for parallel strands: implications for amyloid format. ''Proteins'' 79(11) 3193-3207.

Evidence employing retro-enantio N-methylated peptides, or those with alternating L and D amino acids, as inhibitors of beta-amyloid aggregation is consistent with alpha-sheet being the main material of the amyloid precursor.Grillo-Bosch D, Carulla N, Cruz M, Pujol-Pina R, Madurga S, Rabanal F, Giralt E. (2009). Retro-enantio N-methylated peptides as inhibitors of beta-amyloid aggregation. ''ChemMedChem'' 4, 1488-1494. Kellock J, Hopping G, Cauchey B, Daggett V. (2016). Peptides composed of alternating L- and D-amino acids inhibit amyloidogenesis in three distinct amyloid systems independent of sequence. ''Journal of Molecular Biology'' 428, 2317-2328Paranjapye N, Daggett V. (2018). De novo designed alpha-sheet peptides inhibit functional amyloid formation of Streptococcus mutant biofilms. ''Journal of Molecular Biology'' 430, 3764-3773
Maris NL, Shea D. (2018). Chemical and Physical Variability in Structural Isomers of an L/D
α‑Sheet Peptide Designed To Inhibit Amyloidogenesis. ''Biochemistry'' 57, 507-510. Shea D, Hsu C-C. (2019). α-Sheet secondary structure in amyloid β-peptide drives aggregation and toxicity in Alzheimer’s disease. ''Proc Nat Acad Sci USA'' 116(18) 8895-8900.

References

{{Protein secondary structure

Protein structural motifs