Biophysical Methods

Common folding patterns of protein tertiary structure

[A Tour of Protein Structure] [Biophysical methods home page]

The beta-alpha-beta folding unit is a common feature found in many proteins in which beta sheet (yellow arrow symbols) and alpha helical segments (red ribbons) alternate. The polypeptide starts at lower centre, runs up the left beta strand to the top left, back down the alpha helix and then up the second beta strand in the centre. This arranges the beta strands so that they run parallel.

Alpha helical bundle proteins form when the polypeptide chain is dominated by clusters of amino acids with alpha helix preference (Ala, Leu, Met, Phe, Glu, Gln, Lys, Arg, His). Beta sheet amino acids may be present but are randomly scattered throughout the sequence. The presence of "breaker" amino acids at strategic locations interrupts the helix, allowing the polypeptide to change direction and to fold up into a more compact form. The breaker amino acids are Pro, Gly, Ser, Asn, Asp (plus Thr, an alpha breaker, but relatively common in beta sheets).
The protein shown is myoglobin,depicted as a ribbon tracing the path of the polypeptide chain. The polypeptide forms eight helical segments identified as helix A through H. These are color coded blue at the N-terminus (helix A, B, C) through green (helix D,E,F), yellow (helix G) and red (helix H) at the C-terminus.
Anti-parallel beta sheet proteins form when the polypeptide sequence contains clusters of amino acids with beta sheet preference (Tyr, Trp, Ile Val, Thr, Cys). Alpha helix preferring amino acids are present, but scattered randomly throughout the sequence. The beta sheet strands, shown as yellow arrow symbols, are interrupted by turns (blue) and irregular loops (white) wherever breaker amino acids are located in the polypeptide. One tiny segment of alpha helix is present in one of the connecting loops (red ribbon).
This is the structure of triose phosphate isomerase, an enzyme which has a polypeptide consisting of alternating beta strands (yellow arrow symbols and alpha helix segments (red ribbon). Turns are marked in blue, and loop or random coil in white.
Proteins like this fold as consecutive beta-alpha-beta units, which allows the beta strands to line up into a parallel rather than antiparallel beta sheet. The parallel beta sheet typically has non polar amino acids on both sides. If all the alpha helices line up on one side of the beta sheet, the beta sheet wraps around to form a parallel beta barrel with alpha helix on the outside.
The parallel beta barrel at the core of triose phosphate isomerase. All the arrows run in the same direction. Arrow heads point towards the carboxylate end of each strand.
A view of the parallel beta barrel component of triose phosphate isomerase from above. All atoms are drawn in spacefilling mode, backbone atoms of the beta barrel, carbon, gray; nitrogen, blue; oxygen, red. All side chain atoms are drawn in yellow. Note how the entire central region of the molecule is filled. Although this protein looks like a donut with a hole in the middle, the hole is fully packed with side chains.
A cutaway view of triose phosphate isomerase, seen from above, including the beta barrel core and the alpha helix layer around the outside. Drawn with spacefilling atoms, the beta barrel backbone is drawn in yellow, non-polar amino acids are drawn red and polar amino acids are drawn green. A few traces of blue ribbon near the surface are turn segments containing glycine. The entire beta barrel is dominated by non-polar aminoacids, and non polar amino acids also line the inward facing halves of the alpha helix layer. Only the outer skin of the protein is polar.
A cross section of triose phosphate isomerase viewed from the side. The beta barrel backbone is drawn in yellow, non-polar amino acids are drawn red and polar amino acids are drawn green. A few traces of blue ribbon near the surface are turn segments containing glycine. In this view, the vertical yellow bars are strands of the beta barrel seen in cross section cut across its diameter.
Frontal view of the enzyme lactate dehydrogenase. This is also arranged as alternating segments of beta strand and alpha helix in the unfolded polypeptide chain, folding as a series of beta-alpha-beta units to give a parallel beta sheet at the core. (Helix is red, beta sheet is yellow, turns are blue and random coil is white in this ribbon structure. Unlike triose phosphate isomerase, where the alpha helix always appears on one side of the sheet, lactate dehydrogenase is arranged to place alpha helices on both sides of the beta sheet, resulting in the alpha-beta sandwich tertiary structure. The parallel beta sheet does not fold over on itself so the beta sheet is more or less flat rather than barrel shaped.
Lactate dehydrogenase, 36 kDa, also shows a tertiary structure feature common for larger proteins. The protein has folded into two more or less independent sections, both based on the alpha-beta sandwich. These regions of the folded protein are called domains. Units of the polypeptide spanning 10-20 kDa commonly fold into separate domains, so a polypeptide of 50 kDa may be arranged in 3 or 4 domains. Proteins which fold into multiple domains don't necessarily repeat the same folding pattern as we have seen here for lactate dehydrogenase, but may have alpha helical bundles, and anti-parallel beta sheets and beta-alpha-beta domains all occuring in the same protein, giving the whole molecule a rather more complex appearance.
A side view of lactate dehydrogenase, showing the edge of the beta sheet (yellow) sandwiched between the two layers of alpha helix (red). The edge view reveals that the beta sheets are slightly splayed, which is typical. The narrow neck of polypeptide linking the two domains is also clealy visible on the middle left.

A Tour of Protein Structure

How secondary structure determines folding

Biophysical Methods home page