Alpha sheet (also known as alpha pleated sheet or polar pleated sheet) is an atypical

secondary structure Protein secondary structure is the local spatial conformation of the polypeptide backbone excluding the side chains. The two most common Protein structure#Secondary structure, secondary structural elements are alpha helix, alpha helices and beta ...

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

s, first proposed by

Linus Pauling Linus Carl Pauling ( ; February 28, 1901August 19, 1994) was an American chemist and peace activist. He published more than 1,200 papers and books, of which about 850 dealt with scientific topics. ''New Scientist'' called him one of the 20 gre ...

and

Robert Corey Robert Brainard Corey (August 19, 1897 – April 23, 1971) was an American biochemist, mostly known for his role in discovery of the α-helix and the β-sheet with Linus Pauling. Also working with Pauling was Herman Branson. Their discoveries ...

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 bond In chemistry, a hydrogen bond (H-bond) is a specific type of molecular interaction that exhibits partial covalent character and cannot be described as a purely electrostatic force. It occurs when a hydrogen (H) atom, Covalent bond, covalently b ...

ing pattern in an alpha sheet is similar to that of a

beta sheet The beta sheet (β-sheet, also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a gene ...

, but the orientation of the

carbonyl In organic chemistry, a carbonyl group is a functional group with the formula , composed of a carbon atom double bond, double-bonded to an oxygen atom, and it is divalent at the C atom. It is common to several classes of organic compounds (such a ...

and amino groups in the

peptide bond In organic chemistry, a peptide bond is an amide type of covalent chemical bond linking two consecutive alpha-amino acids from C1 (carbon number one) of one alpha-amino acid and N2 (nitrogen number two) of another, along a peptide or protein cha ...

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 An alpha helix (or α-helix) is a sequence of amino acids in a protein that are twisted into a coil (a helix). The alpha helix is the most common structural arrangement in the Protein secondary structure, secondary structure of proteins. It is al ...

and

, the alpha sheet configuration does not require all component

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

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 structure Protein structure is the three-dimensional arrangement of atoms in an amino acid-chain molecule. Proteins are polymers specifically polypeptides formed from sequences of amino acids, which are the monomers of the polymer. A single amino acid ...

s, 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

amyloid Amyloids are aggregates of proteins characterised by a fibrillar morphology of typically 7–13 nm in diameter, a β-sheet secondary structure (known as cross-β) and ability to be stained by particular dyes, such as Congo red. In the human ...

ogenic proteins in

molecular dynamics Molecular dynamics (MD) is a computer simulation method for analyzing the Motion (physics), physical movements of atoms and molecules. The atoms and molecules are allowed to interact for a fixed period of time, giving a view of the 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 X-ray crystallography is the experimental science of determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to Diffraction, diffract in specific directions. By measuring th ...

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 Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid. Glycine is one of the proteinogenic amino acids. It is encoded by all the codons starting with GG (G ...

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

, 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 Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the p ...

threonine Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form when dissolved in water), a carboxyl group (which is in the deprotonated −COO− ...

valine Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deproton ...

and

isoleucine Isoleucine (symbol Ile or I) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...

, 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 Fiber diffraction is a subarea of scattering, an area in which molecular structure is determined from scattering data (usually of X-rays, electrons or neutrons). In fiber diffraction, the scattering pattern does not change, as the sample is rota ...

results from beta-keratin fibers. However, since the alpha sheet did not appear to be energetically favorable, they argued that

s 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 In biochemistry, the native state of a protein or nucleic acid is its properly Protein folding, folded and/or assembled form, which is operative and functional. The native state of a biomolecule may possess all four levels of biomolecular structu ...

proteins as solved by

protein NMR Nuclear magnetic resonance spectroscopy of proteins (usually abbreviated protein NMR) is a field of structural biology in which NMR spectroscopy is used to obtain information about the structure and dynamics of proteins, and also nucleic acids, and ...

, 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 Synaptotagmins (SYTs) constitute a family of cell membrane, membrane-trafficking proteins that are characterized by an N-terminal transmembrane region (TMR), a variable linker, and two C-terminal C2 domains - C2A and C2B. There are 17 Protein isof ...

lysozyme Lysozyme (, muramidase, ''N''-acetylmuramide glycanhydrolase; systematic name peptidoglycan ''N''-acetylmuramoylhydrolase) is an antimicrobial enzyme produced by animals that forms part of the innate immune system. It is a glycoside hydrolase ...

, 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

s. 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 di

phenyl In organic chemistry, the phenyl group, or phenyl ring, is a cyclic group of atoms with the formula , and is often represented by the symbol Ph (archaically φ) or Ø. The phenyl group is closely related to benzene and can be viewed as a benzene ...

-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 biochemistry, a conformational change is a change in the shape of a macromolecule, often induced by environmental factors. A macromolecule is usually flexible and dynamic. Its shape can change in response to changes in its environment or othe ...

in the formation of

fibrils by

peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...

s and proteins such as

amyloid beta Amyloid beta (Aβ, Abeta or beta-amyloid) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor prot ...

, poly-glutamine repeats,

prion A prion () is a Proteinopathy, misfolded protein that induces misfolding in normal variants of the same protein, leading to cellular death. Prions are responsible for prion diseases, known as transmissible spongiform encephalopathy (TSEs), w ...

proteins, and

transthyretin Transthyretin (TTR or TBPA) is a transport protein in the plasma and cerebrospinal fluid that transports the thyroid hormone thyroxine (T4) and retinol to the liver. This is how transthyretin gained its name: ''transports thyroxine and retinol' ...

repeats, all of which are associated with protein misfolding disease. For example, amyloid beta is a major component of

amyloid plaque Amyloid plaques (also known as neuritic plaques, amyloid beta plaques or senile plaques) are extracellular deposits of amyloid beta (Aβ) protein that present mainly in the grey matter of the brain. Degenerative neuronal elements and an abunda ...

s in the brains of

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

patients, and polyglutamine repeats in the

huntingtin Huntingtin (Htt) is the protein coded for in humans by the ''HTT'' gene, also known as the ''IT15'' ("interesting transcript 15") gene. Mutation, Mutated ''HTT'' is the cause of Huntington's disease (HD), and has been investigated for this role an ...

protein are associated with

Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is an incurable neurodegenerative disease that is mostly Genetic disorder#Autosomal dominant, inherited. It typically presents as a triad of progressive psychiatric, cognitive, and ...

.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

from largely

random coil In polymer chemistry, a random coil is a conformation of polymers where the monomer subunits are oriented randomly while still being bonded to adjacent units. It is not one specific shape, but a statistical distribution of shapes for all the cha ...

structures to the highly ordered

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 Protein primary structure is the linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the amino-terminal (N) end to the carboxyl-terminal (C) end. Protein biosynthe ...

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

is among the few native-state proteins shown to contain an alpha-strand region; lysozyme from both

chicken The chicken (''Gallus gallus domesticus'') is a domesticated subspecies of the red junglefowl (''Gallus gallus''), originally native to Southeast Asia. It was first domesticated around 8,000 years ago and is now one of the most common and w ...

s and

human Humans (''Homo sapiens'') or modern humans are the most common and widespread species of primate, and the last surviving species of the genus ''Homo''. They are Hominidae, great apes characterized by their Prehistory of nakedness and clothing ...

s contains an alpha strand located close to the site of a

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

known to cause hereditary amyloidosis in humans, usually an

autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...

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