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The Family of Beta-Helical Structures in Proteins

The Family of Beta-Helical Structures in Proteins
S. J. Kennedy1, H.R. Besch. Jr.2
The right-handed parallel beta helix is a structural motif that has been experimentally
observed in a range of proteins (1). A database screening algorithm recently found ~2400
putative beta-helical proteins (2). This communication reviews briefly the structural
principles of beta helices, a family of helical protein conformations predicted on
theoretical grounds more than 25 years ago.
Kennedy and coworkers (3-5) proposed a family of regular helical protein
conformations having nonequivalent residues. They identified the four local residue
conformations able to participate in a parallel hydrogen-bonding scheme, and illustrated
how these could be combined to form maximally hydrogen-bonded helical structures.
Two of the local conformations (β and βD) are identical to those found in parallel betapleated sheets of all-L or all-D amino acids, and the other two are roughly equivalent to
those in the right- and left-handed alpha helices. We labeled the latter two as δ1 and δ2 to
emphasize the fact that, in a beta helix, these residues do not display the usual 1 → 4
hydrogen-bonding pattern of an alpha helix. Nevertheless, these residues are located in
the low energy regions of the Ramachandran plot normally associated with right- and
left-handed alpha helices, and we refer to them herein as αR and αL to conform with the
current literature.
In a beta helix, strands of beta sheet are interrupted by residues in the αR or αL
conformation. These residues cause the beta strands to bend while allowing the
hydrogen-bonding pattern to be maintained. A full turn of the helix is completed when
sufficient bends are present to form a closed irregular polygon, and this pattern of α and
β residues is repeated for each turn of the helix. All peptide bonds in the helix are
oriented parallel or antiparallel to the axis of the helix and each residue is hydrogenbonded to a similarly oriented residue in the turns of the helix immediately above and
below it.
In proteins of the pectate lyase family, the body of the beta helix is "exploded"
outward in several places where segments of the helix are replaced by large loops of nonregular structure. Rarely in these proteins does the polypeptide chain trace even one
complete, uninterrupted turn of beta helix. Nevertheless, the characteristic features of the
beta helix are apparent. The lyase family beta helix has 22 residues per turn, the bends
being formed by four αL and two αR residues. A single turn of the cognate beta-22 helix
is shown in Figure 1a.
Figure 1. A. A single turn of the beta-22
helix. For clarity only the beta-carbon
atoms of side chains are shown. The
polypeptide chain proceeds
counterclockwise around the turn. The
four-residue beta-sheets PB1, PB2 and
PB3 and the two-residue sheet PB1a (1)
are indicated. Single αL residues form
the bends T1, T1a and T2 at the ends of
sheets PB1, PB1a and PB2, respectively.
Turn T3 at lower left is formed by the
five-residue pattern αL-β-αR-β-αR.
B. Ramachandran plot of the residues in
the Rhamnogalacturonase A beta-helix.
Contours denote low energy regions for
non-glycine residues. Groups of β,
α L,
αR and βD residues are marked. Open
symbols represent glycine residues.
The most regular beta helix in the lyase family is found in Rhamnogalacturonase A.
The PB1a sheet is well formed, and the pattern of residues in the T3 turn is clearly
evident. A Ramachandran plot of the amino acid residues participating in the beta helix
shows the groups of β, αR and αL residues, along with a few glycine residues in the βD
conformation (Figure 1b). This plot substantiates the experimental realization of the four
residue types predicted to occur in beta-helical structures (3,5). An interactive graphical
display of the Rhamnogalacturonase A beta helix is provided in the supplementary
material (6).
Because of their relatively large size, beta helices can exhibit considerable steric
plasticity, and various members of the lyase family show distortions from the idealized
helix shown in Figure 1a. For example, the P22 viral tailspike protein has an extra αR
residue inserted into the T3 region in each of six successive turns of the helix so that the
pattern there is a distorted version of αL-β-αR-αR-β-αR. Also, several members of the
family do not display a recognizable PB1a sheet. Jenkins and Pickersgill (1) provide a
comprehensive discussion of the structural differences in the lyase family beta helices.
While beta helices related to the lyase family may be restricted to bacterial and fungal
proteins (2), recent evidence has uncovered a different beta helix in the C-terminal actinbinding domain of the yeast adenylyl cyclase-associated protein, CAP, which has
sequence homologues in humans and higher eukaryotes (7). This helix (1KQ5 in the
RCSB Protein Data Bank) is approximately rectangular in cross section, and appears
related to the lyase family helix in its well defined T1, PB1a and T1a, like those of the
beta-22 helix of Figure 1. It differs in that PB1 and PB2 contain five β residues rather than
four and PB3 is possibly only two residues in length. The exact pattern in the
neighborhood of T2, PB3 and T3 is difficult to ascertain because the protein is fairly
disordered in this area, but αR residues are common there. A satisfactory pattern of
residues that would close the loop is αR-β-β-αR. This would produce a beta-18 helix with
two αL and two αR residues per turn.
Beta-helical structures have been found (see references in (1)) in proteins as diverse
as the insulin-like growth factor receptor, antifreeze proteins, spliceosomal proteins, the
DNA-injecting needle of bacteriophage T4 (8), and human ribonuclease inhibitor, whose
exquisite symmetry wraps a stack of half turns of beta helix in a halo of alpha helices.
Search algorithms optimized to identify beta helices related to CAP portend many more
members of the family of beta-helical proteins. Logical predictions of long ago are now
coming to fulfillment in the proteomics era.
1. J. Jenkins, R. Pickersgill, Prog. Biophys. Mol. Biol. 77, 111 (2001).
2. P. Bradley, L. Cowen, M. Menke, J. King, B. Berger, Proc. Natl. Acad. Sci. U.S.A. 98,
14819 (2001).
3. S. J. Kennedy, H. R. Besch, Jr., A. M. Watanabe, A. R Freeman, R. W. Roeske, in
Peptides: Proceedings of the Fifth American Peptide Symposium, M. Goodman, J.
Meienhofer, Eds. (Wiley, New York, 1977), pp. 423-426.
4. S. J. Kennedy, R. W. Roeske, A. R Freeman, A. M. Watanabe, H. R. Besch, Jr.,
Science 196, 1341 (1977).
5. S. J. Kennedy, J Membr Biol. 42, 265 (1978).
6. Supplementary figures are available on Science Online at www.sciencemag.org/????.
7. A. A. Fedorov, T. Dodatko, D. A. Roswarski, S. C. Almo, in preparation.
8. S. Kanamaru et al., Nature 415, 553 (2002).
Technology Development Center, Georgia Institute of Technology, Atlanta,
GA 30318, USA. 2Department of Pharmacology, Indiana University School of Medicine,
Indianapolis, IN 46202, USA.