Beta hairpin

Last updated August 22, 2021

The beta hairpin (sometimes also called beta-ribbon or beta-beta unit) is a simple protein structural motif involving two beta strands that look like a hairpin. The motif consists of two strands that are adjacent in primary structure, oriented in an antiparallel direction (the N-terminus of one sheet is adjacent to the C-terminus of the next), and linked by a short loop of two to five amino acids. Beta hairpins can occur in isolation or as part of a series of hydrogen bonded strands that collectively comprise a beta sheet.

Classification

Beta hairpins were originally categorized solely by the number of amino acid residues in their loop sequences, such that they were named one-residue, two-residue, etc.^[2] This system, however, is somewhat ambiguous as it does not take into account whether the residues that signal the end of the hairpin are singly or doubly hydrogen bonded to one another. An improved means of classification has since been proposed by Milner-White and Poet.^[3] Beta hairpins are broken into four distinct classes as depicted in the publication's Figure 1. Each class begins with the smallest possible number of loop residues and progressively increases the loop size by removing hydrogen bonds in the beta sheet. The primary hairpin of class 1 is a one-residue loop where the bound residues share two hydrogen bonds. One hydrogen bond is then removed to create a three-residue loop, which is the secondary hairpin of class 1. Singly bound residues are counted in the loop sequence but also signal the end of the loop, thus defining this hairpin as a three-residue loop. This single hydrogen bond is then removed to create the tertiary hairpin; a five-residue loop with doubly bound residues. This pattern continues indefinitely and defines all beta hairpins within the class. Class 2 follows the same pattern beginning with a two-residue loop with terminating residues that share two hydrogen bonds. Class 3 begins with a three-residue, and class 4 with a four-residue. Class 5 does not exist as that primary hairpin is already defined in class 1. Pi This classification scheme not only accounts for various degrees of hydrogen bonding, but also says something about the biological behavior of the hairpin. Single amino acid replacements may destroy a particular hydrogen bond, but will not unfold the hairpin or change its class. On the other hand, amino acid insertions and deletions will have to unfold and reform the entire beta strand in order to avoid a beta bulge in the secondary structure. This will change the class of the hairpin in the process. As substitutions are the most common amino acid mutations, a protein could potentially undergo a conversion without affecting the functionality of the beta hairpin.^[3]

Folding and binding dynamics

Native turn region of a beta-hairpin Native turn.png — Native turn region of a beta-hairpin

The Pin1 Domain. Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) - a 34-residue protein - is depicted above in two different ways. On the left, the reverse turns are easily seen in green, while the b-strands are seen in yellow. These come together to create a b-hairpin motif. The figure on the right depicts the same enzyme in a more three-dimensional aspect. Bj1.png — The Pin1 Domain. Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) – a 34-residue protein – is depicted above in two different ways. On the left, the reverse turns are easily seen in green, while the β-strands are seen in yellow. These come together to create a β-hairpin motif. The figure on the right depicts the same enzyme in a more three-dimensional aspect.

Understanding the mechanism through which micro-domains fold can help to shed light onto the folding patterns of whole proteins. Studies of a beta hairpin called chignolin (see Chignolin on Proteopedia) have uncovered a stepwise folding process that drives beta-hairpin folding. This hairpin has sequence features similar to over 13,000 known hairpins, and thus may serve as a more general model for beta hairpin formation. The formation of a native turn region signals the folding cascade to start, where a native turn is one that is present in the final folded structure.

In the folding of overall proteins, the turn may originate not in the native turn region but in the C-strand of the beta-hairpin. This turn then propagates through the C-strand (the beta strand leading to C-terminus) until it reaches the native turn region. Sometimes the residue interactions leading up to the native turn region are too strong, causing reverse propagation. However, once the native turn does form, interactions between prolines and tryptophan residues (seen in image at right) in the region help to stabilize the turn, preventing "roll back" or dissolution.

Researchers believe that turns do not originate in the N-strand, due to increased rigidity (often caused by a proline leading up to the native turn region) and less conformational options. The initial turn formation takes place in about 1 μs. Once the initial turn has been established, two mechanisms have been proposed as to how the rest of the beta-hairpin folds: a hydrophobic collapse with side-chain level rearrangements, or the more accepted zipper-like mechanism.^[4]

The β-hairpin loop motif can be found in many macromolecular proteins. However, small and simple β-hairpins can exist on their own as well. To see this clearly, the Pin1 Domain protein is shown to the left as an example.

Proteins that are β-sheet rich, also called WW domains, function by adhering to proline-rich and/or phosphorylated peptides to mediate protein–protein interactions. The "WW" refers to two tryptophan (W) residues that are conserved within the sequence and aid in the folding of the β-sheets to produce a small hydrophobic core.^[5] These tryptophan residues can be seen below (right) in red.

This enzyme binds its ligand through van der Waals forces of the conserved tryptophans and the proline-rich areas of the ligand. Other amino acids can then associate with the hydrophobic core of the β-hairpin structure to enforce secure binding.^[6]

It is also common to find proline residues within the actual loop portion of the β-hairpin, since this amino acid is rigid and contributes to the "turn" formation. These proline residues can be seen as red side chains in the image of the Pin1 WW domain below (left).

Pin1 wwdomain-Proline-rich loops Bj3.png — Pin1 wwdomain-Proline-rich loops

Pin1 wwdomain-Conserved Tryptophans Bj2.png — Pin1 wwdomain-Conserved Tryptophans

Artificially designed beta-hairpin

The design of peptides that adopt β-hairpin structure (without relying on metal binding, unusual amino acids, or disulfide crosslinks) has made significant progress and yielded insights into protein dynamics. Unlike α-helices, β-hairpins are not stabilized by a regular hydrogen bonding pattern. As a result, early attempts required at least 20–30 amino acid residues to attain stable tertiary folds of β-hairpins. However, this lower limit was reduced to 12 amino acids by the stability gains conferred by the incorporation of tryptophan-tryptophan cross-strand pairs. Two nonhydrogen-bonding tryptophan pairs have been shown to interlock in a zipper-like motif, stabilizing the β-hairpin structure while still allowing it to remain water-soluble. The NMR structure of a tryptophan zipper (trpzip) β-peptide shows the stabilizing effect of favorable interactions between adjacent indole rings.^[7]

azobenzene hairpin Jl2.png — azobenzene hairpin

The synthesis of trpzip β-hairpin peptides has incorporated photoswitches that facilitate precise control over folding. Several amino acids in the turn are replaced by azobenzene, which can be induced to switch from the trans to the cis conformation by light at 360 nm. When the azobenzene moiety is in the cis conformation, the amino acid residues align correctly to adopt a β-hairpin formation. However, the trans conformation does not have proper turn geometry for the β-hairpin.^[8] This phenomenon can be used to investigate peptide conformational dynamics with femtosecond absorption spectroscopy.^[8]

Related Research Articles

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Protein secondary structure is the three dimensional form of local segments of proteins. The two most common secondary structural elements are alpha helices and beta sheets, though beta turns and omega loops occur as well. Secondary structure elements typically spontaneously form as an intermediate before the protein folds into its three dimensional tertiary structure.

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In a chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a common three-dimensional structure that appears in a variety of different, evolutionarily unrelated molecules. A structural motif does not have to be associated with a sequence motif; it can be represented by different and completely unrelated sequences in different proteins or RNA.

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A beta bulge can be described as a localized disruption of the regular hydrogen bonding of beta sheet by inserting extra residues into one or both hydrogen bonded β-strands.

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Prolyl isomerase is an enzyme found in both prokaryotes and eukaryotes that interconverts the cis and trans isomers of peptide bonds with the amino acid proline. Proline has an unusually conformationally restrained peptide bond due to its cyclic structure with its side chain bonded to its secondary amine nitrogen. Most amino acids have a strong energetic preference for the trans peptide bond conformation due to steric hindrance, but proline's unusual structure stabilizes the cis form so that both isomers are populated under biologically relevant conditions. Proteins with prolyl isomerase activity include cyclophilin, FKBPs, and parvulin, although larger proteins can also contain prolyl isomerase domains.

A leucine-rich repeat (LRR) is a protein structural motif that forms an α/β horseshoe fold. It is composed of repeating 20–30 amino acid stretches that are unusually rich in the hydrophobic amino acid leucine. These tandem repeats commonly fold together to form a solenoid protein domain, termed leucine-rich repeat domain. Typically, each repeat unit has beta strand-turn-alpha helix structure, and the assembled domain, composed of many such repeats, has a horseshoe shape with an interior parallel beta sheet and an exterior array of helices. One face of the beta sheet and one side of the helix array are exposed to solvent and are therefore dominated by hydrophilic residues. The region between the helices and sheets is the protein's hydrophobic core and is tightly sterically packed with leucine residues.

Protegrins are small peptides containing 16-18 amino acid residues. Protegrins were first discovered in porcine leukocytes and were found to have antimicrobial activity against bacteria, fungi, and some enveloped viruses. The amino acid composition of protegrins contains six positively charged arginine residues and four cysteine residues. Their secondary structure is classified as cysteine-rich β-sheet antimicrobial peptides, AMPs, that display limited sequence similarity to certain defensins and tachyplesins. In solution, the peptides fold to form an anti-parallel β-strand with the structure stabilized by two cysteine bridges formed among the four cysteine residues. Recent studies suggest that protegrins can bind to lipopolysaccharide, a property that may help them to insert into the membranes of gram-negative bacteria and permeabilize them.

β turns are the most common form of turns—a type of non-regular secondary structure in proteins that cause a change in direction of the polypeptide chain. They are very common motifs in proteins and polypeptides. Each consists of four amino acid residues. They can be defined in two ways: 1. By the possession of an intra-main-chain hydrogen bond between the CO of residue i and the NH of residue i+3; Alternatively, 2. By having a distance of less than 7Å between the Cα atoms of residues i and i+3. The hydrogen bond criterion is the one most appropriate for everyday use, partly because it gives rise to four distinct categories; the distance criterion gives rise to the same four categories but yields additional turn types.

The Nest is a type of protein structural motif. It is a small recurring anion-binding feature of both proteins and peptides. Each consists of the main chain atoms of three consecutive amino acid residues. The main chain NH groups bind the anions while the side chain atoms are often not involved. Proline residues lack NH groups so are rare in nests. About one in 12 of amino acid residues in proteins, on average, belongs to a nest.

Schellman loops are commonly occurring structural features of proteins and polypeptides. Each has six amino acid residues with two specific inter-mainchain hydrogen bonds and a characteristic main chain dihedral angle conformation. The CO group of residue i is hydrogen-bonded to the NH of residue i+5, and the CO group of residue i+1 is hydrogen-bonded to the NH of residue i+4. Residues i+1, i+2, and i+3 have negative φ (phi) angle values and the phi value of residue i+4 is positive. Schellman loops incorporate a three amino acid residue RL nest, in which three mainchain NH groups form a concavity for hydrogen bonding to carbonyl oxygens. About 2.5% of amino acids in proteins belong to Schellman loops. Two websites are available for examining small motifs in proteins, Motivated Proteins: ; or PDBeMotif:.

Beta bulge loops are commonly occurring motifs in proteins and polypeptides consisting of five to six amino acids. There are two types: type 1, which is a pentapeptide; and type 2, with six amino acids. They are regarded as a type of beta bulge, and have the alternative name of type G1 beta bulge. Compared to other beta bulges, beta bulge loops give rise to chain reversal such that they often occur at the loop ends of beta hairpins; hairpins of this sort can be described as 3:5 or 4:6. Two websites are available for finding and examining β bulge loops in proteins, Motivated Proteins: and PDBeMotif:.

References

↑ Blanco, F. J.; Rivas, G.; Serrano, L. (1994). "A short linear peptide that folds into a native stable beta-hairpin in aqueous solution". Nat Struct Biol. 1 (9): 584–590. doi:10.1038/nsb0994-584. PMID 7634098. S2CID 35065527.
↑ Sibanda, B.L.; Blundell, T.L.; Thorton, J.M. (1985). "Conformations of Beta-Hairpins in Protein Structures". Nature(London) 316 170–174.
1 2 Milner-White, J.; Poet, R. (1986). "Four Classes of Beta-Hairpins in Proteins". Biochemical Journal 240 289–292.
1 2 Enemark, Søren; Kurniawan, Nicholas A.; Rajagopalan, Raj (11 September 2012). "β-hairpin forms by rolling up from C-terminal: Topological guidance of early folding dynamics". Scientific Reports. 2: 649. Bibcode:2012NatSR...2E.649E. doi:10.1038/srep00649. PMC 3438464 . PMID 22970341.
↑ Jager, Marcus; Deechongkit, Songpon; Koepf, Edward K.; Nguyen, Houbi; Gao, Jianmin; Powers, Evan T.; Gruebele, Martin; Kelly, Jeffery W. (2008). "Understanding the mechanism of β-sheet folding from a chemical and biological perspective". Biopolymers. 90 (6): 751–758. doi:10.1002/bip.21101. PMID 18844292.
↑ Kay, B.K.; Williamson, M.P.; Sudol, M. The Importance of Being Proline: the interaction of proline-rich motifs in signaling proteins with their cognate domains. The FASEB Journal. 2000, 14, 231–241.
↑ Cochran, Andrea G.; Skelton, Nicholas J.; Starovasnik, Melissa A. (8 May 2001). "Tryptophan zippers: Stable, monomeric β-hairpins". Proceedings of the National Academy of Sciences. 98 (10): 5578–5583. Bibcode:2001PNAS...98.5578C. doi: 10.1073/pnas.091100898 . ISSN 0027-8424. PMC 33255 . PMID 11331745.
1 2 Dong, Shou-Liang; Löweneck, Markus; Schrader, Tobias E.; Schreier, Wolfgang J.; Zinth, Wolfgang; Moroder, Luis; Renner, Christian (23 January 2006). "A Photocontrolled β-Hairpin Peptide". Chemistry – A European Journal. 12 (4): 1114–1120. doi:10.1002/chem.200500986. ISSN 1521-3765. PMID 16294349.

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[Blanco-1] Blanco, F. J.; Rivas, G.; Serrano, L. (1994). "A short linear peptide that folds into a native stable beta-hairpin in aqueous solution". Nat Struct Biol. 1 (9): 584–590. doi:10.1038/nsb0994-584. PMID 7634098. S2CID 35065527.

[2] Sibanda, B.L.; Blundell, T.L.; Thorton, J.M. (1985). "Conformations of Beta-Hairpins in Protein Structures". Nature(London) 316 170–174.

[Milner-White-3] 1 2 Milner-White, J.; Poet, R. (1986). "Four Classes of Beta-Hairpins in Proteins". Biochemical Journal 240 289–292.

[C-terminal_p._2,_649-4] 1 2 Enemark, Søren; Kurniawan, Nicholas A.; Rajagopalan, Raj (11 September 2012). "β-hairpin forms by rolling up from C-terminal: Topological guidance of early folding dynamics". Scientific Reports. 2: 649. Bibcode:2012NatSR...2E.649E. doi:10.1038/srep00649. PMC 3438464 . PMID 22970341.

[Jager-5] Jager, Marcus; Deechongkit, Songpon; Koepf, Edward K.; Nguyen, Houbi; Gao, Jianmin; Powers, Evan T.; Gruebele, Martin; Kelly, Jeffery W. (2008). "Understanding the mechanism of β-sheet folding from a chemical and biological perspective". Biopolymers. 90 (6): 751–758. doi:10.1002/bip.21101. PMID 18844292.

[6] Kay, B.K.; Williamson, M.P.; Sudol, M. The Importance of Being Proline: the interaction of proline-rich motifs in signaling proteins with their cognate domains. The FASEB Journal. 2000, 14, 231–241.

[7] Cochran, Andrea G.; Skelton, Nicholas J.; Starovasnik, Melissa A. (8 May 2001). "Tryptophan zippers: Stable, monomeric β-hairpins". Proceedings of the National Academy of Sciences. 98 (10): 5578–5583. Bibcode:2001PNAS...98.5578C. doi: 10.1073/pnas.091100898 . ISSN 0027-8424. PMC 33255 . PMID 11331745.

[:0-8] 1 2 Dong, Shou-Liang; Löweneck, Markus; Schrader, Tobias E.; Schreier, Wolfgang J.; Zinth, Wolfgang; Moroder, Luis; Renner, Christian (23 January 2006). "A Photocontrolled β-Hairpin Peptide". Chemistry – A European Journal. 12 (4): 1114–1120. doi:10.1002/chem.200500986. ISSN 1521-3765. PMID 16294349.

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