Structure of Coiled Fp-Hairpins and P P-Corners

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Volume 284, number 2, 288-202 FEES 0985 1 June 1991 0 1991 Federation of European Biochemical Societies 00145793/91/43.50 ADONIS 001457939100561U Structure of coiled Fp-hairpins and P_P-corners

A.V. Efimov

Instilureqf Protein Research, Academy of Scierrces of the USSR, 142292 Pushchino. Moscow Region, USSR

Received 9 April 199 1

Two types of super-secondary structure, coiled kp-hairpins and P_&corners, are considered in this paper. A P_@orner can be represented as a long &/I-hairpin folded orthogonally on itself so that the strands, when passing from one layer to the other. rotate in a right-handed direction about an imaginary axis. It is shown that a /?--~-hairpin. forming a coiled coil structure or a /I-/l-corner. is right-handed when viewed from the concave side. These unique arrangements of /?-strands in the coiled /I-p-hairpins and /Y-/korners are of particular value in protein modclling and prediction.

Antiparallel j&sheet: Conformation: Protein: Strand: Structure

1. INTRODUCTION for the residues in the large and small rings, respectively, as used by Salemme and Weather ford [3]. The inter- In a P-P-hairpin, a polypeptide chain folds back on chain Cp-atom contact distances are different for the itself so that the two adjacent strands form an an- large and small hydrogen-bonded rings and are equal to tiparallel &sheet. &&Hairpins are widespread in pro- 3.7 A and 5.7 A, respectively. teins and occur both as isolated, double-strand an- An extended polypeptide chain with identical v, rl, tiparallel B-sheets and parts of multiple-strand P-sheets. values is straight and has a structure corresponding to a When viewed along the polypeptide chain direction, the strand in a flat or moderately twisted &sheet. To form &sheets in proteins are almost invariably twisted in a a coiled coil with the appropriate right-handed direction right-handed sense [ 11. To maintain a large contact area the strands must have cp, $ values which fulfill the without disturbing the hydrogen bonds, the strands following conditions [5]: must be coiled as well as twisted in the strongly twisted P-sheets [2,3]. Gi’-Vi+19 $i+ I > -(ci+Z, $i+Z z -Vi+39 $i+3 > P-&Hairpins can be right- or left-handed depending -(di+d, -s- on whether the second P-strand runs on the right or left, relative to the first one when viewed from the same side A coiled coil structure of a double-strand antiparallel /3- (e.g. as viewed from the hydrophobic core). A /3-P- sheet in which these conditions are fulfilled is shown in hairpin can be coiled into a right-handed double-strand Fig, 1b. This coiled coil can be represented as a double- superhelix or folded into a a-P-corner. A /.%&corner helical structure in which the strands are twisted and can be represented as a long P-P-hairpin folded or- coiled in a right-handed sense. The structure has both a thogonally on itself so that P-strands cross from one convave and a convex surface. The side chains of the layer to the other while bending by 90’. The main result residues included in the small hydrogen-bonded rings of this paper is that coiled coils and B-P-corners are (their main chain torsion angles are denoted as cps, $s) formed by right-handed P-P-hairpins if they are viewed are situated on the concave surface or ‘inside’ while the from the concave side of a coiled coil or a &&corner. side chains of the residues included in the large rings

(having (PL, $L angles) are situated on the convex surface or ‘outside’ the double-helical structure. One more 2. COILED COIL STRUCTURE OF &P-HAIRPINS feature of this structure is that the cp, $ values alternate Fig. la shows a fragment of a classical flat an- along the polypeptide chains [2,3,5]. Fig. 2 shows how tiparallel a-sheet structure [4]. There are large and small these cp, $ values alternate in strongly twisted and coiled hydrogen-bonded rings in the structure and the main antiparallel P-sheets in bovine pancreatic trypsin in- chain torsion angles are denoted as (oI_, $I_ and ps, $s hibitor (61, lactate dehydrogenase [7], alcohol dehydrogenase [8] and interleukin-l/3 [9]. As a rule, the PS values are lower than the pt. values while the $s values Corresporrdorce nddress: A.V. Efimov, Institute of Protcin Kcscarcli, Acildctny of Scicnccs of the I!SSH. 142292 Pushchino, Moscow are higher than the $1. values. In other words, the cps, $S Region, USSR values fall in the upper left corner of the sterically Volume 284, number 2 FEBS LETTERS June 1991

that shifting the cp~, $L values to the upper left corner of the Ramachandran map results in a great decrease of the interchain Co-atom distances in the large hydrogen- bonded rings and, consequently, in great sterical hin- drances. It is noteworthy that shifting the VL, $I_ values to the polyproline helix region, as in the structure shown in Fig. lb, results in an increase of these distances which are sterically favourable. On the other hand, it is impossible to shift the cps, $S values to the polyproline helix region without disturbing the hydrogen bond patterns. It should be also noted that residues with CAL,$L angles do not form hydrogen bonds and that shifting the (PL, 4~ values to the polyproline helix region (as shown in Fig. 1) does not affect the interchain hydrogen bonds.

3. /3-&CORNERS N c A @&corner structure can be represented as a long N B-&hairpin folded on itself so that the P-strands of the a) b) two halves are packed orthogonally in the two different layers. P-P-Corners are right-handed in proteins of Fig. I. A schematic representation of flat (a) and coiled (b) double- strand antiparallel P-sheets. Main chain torsion angles are denoted as known structure. This means that the strands rotate

PL, $L and PS, $S for the large and small rings, respectively. Also see about an imaginary axis in the right-handed direction the test. when passing from one &sheet to the other (see Fig. 4a,b). There are some types of P-&corners which differ allowed P-region and VI_, $L values fall in the right half from each other in the structure of the bending site, i.e. of the ®ion close to the region of polyproline helix the site where the P-strands cross from one layer to the conformations. An analysis shows that inside residues other while bending by 90’. There are &&corners in can have (p, $ values up to p = - 180°, $ = 180” and which this site is a fragment of a double-stranded coiled even e-conformations (for e-conformations see [lo]) coil considered above. The residues of such a bending from the bottom right quadrant of the Ramachandran site form hydrogen bonds and have the appropriate map if these residues are glycines. Prolines in the out- alternation of cp, $ values as in the coiled coil. In many side positions, however, have to facilitate the formation cases one of the inside positions in such a site is oc- of a coiled coil. Inside positions cannot be occupied by cupied by glycine having a very extended conformation prolines since very extended conformations are forbid- (up to cp = - 180”, II, = 180’) or an E-conformation. den for them and they prevent from hydrogen bonding &P-Corners of this type are formed by right-handed in these positions. /3-P-hairpins when viewed from the concave side (Fig. If the strands in the coiled antiparallel D-sheet shown 4a). Such &&corners are observed, for example, in the in Fig. 1b are connected by a loop, there is a right- regions 52-78 and 85-105 of retinol binding protein handed &&hairpin when viewed from the concave [l l], 9-24 and 41-60 of acetyl-pepstatin-bound HIV-l side. This is a structure that occurs in proteins [6-91. It protease [ 121, 266-294 of lactate dehydrogenase [7]. It should be noted that this coiled &&hairpin is left- should be noted that &&corners of this type and P-P- handed when viewed from the convex side. hairpin coiled coils have similar structures and, in some It is impossible to coil a ,0-P-hairpin in a different cases, it is difficult to differentiate one from another. A way, so that it would be a left-handed &&hairpin when feature of @@-corners is that their P-strands, as a rule, viewed from the concave side (Fig. 3d), In such a coiled interact with other P-strands in one or both orthogonal- coil structure inside residues (situated on the concave ly packed &sheets. side) would be the residues included in the large In another type of P-P-corners the strands have dif- hydrogen-bonded rings and the outside residues would ferent conformations in the bending site. One strand be those of the small rings. This means that the (PL, $L has a conformation similar to that in a coiled coil with values of this structure should fall in the upper left cor- the appropriate alternation of ~0,\I, values. A P-strand in ner of the P-region and that the cos, & should fall close the so-called P-band [13] also has a similar structure to the polyproline helix region. But this is not consistent (/3-P-corners are not to be confused with P-bends in with the energy calculations [3) and cp, $ distributions in which the only P-strand crosses from one layer to the proteins (see Fig. 2). A stereochemical analysis shows other). There can be glycine in one of the inside posi-

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180 180 1

140

V I 100 I 100 I t

60 1 60 -180 -140 -100 -60 -180 -140 -100 -60 cp cp

a) b)

180 180 4

140

Y Y

100 100

IP2-A 1 I \I 60 I I I 60 -180 -140 -100 -60 -180 -140 -100 -60 Y 'p

c) d)

Fig. 2. Distribution of q, $ values in coiled /3-b-hairpins from known proteins: (a) strands 19-24 and 29-34, of BPTI [6]; (b) strands 268-273 and 284-290, of LDH (71; (c) strands I-14 and 21-29, of ADH [a]; (d) strands 68-74 and 77-83 of interlcukin-10 191. Open circles show +q., $1. values, and solid circles show qps, $Svalues. The thin lines connect (p, 3 values of one P-strand and the dotrcd lines connect p, $ values of the other a-strand of a coiled &&hairqin. tions of this strand with an E- or very extended confor- 63-87, 83-105, 191-211 of peniciliipepsin [15], 61-74 mation. The other strand can have a P-bulge [14] or a and 72-109 of ribonuclease S [16], and 57-77 of HIV-l small standard structure with a /3c@3-, PkL?-, &x$3- protease [12], etc. or /3yy&conformation [IO] each of which provides a There are p-p-corners in which both the strands pass 90” bend and a cross-over of the polypeptide chain from one layer to the other and bend through a right from one layer to the other. &&Hairpins forming p-/3- angle over a few residues forming one of the small stan- corners of this type are right-handed when viewed from dard structures described in [IO], the so-called cross- the concave side. Such P-B-corners are found in regions overs or half-turns having P&3-, /3/3c~3-,Pay&, L$r(3-

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a) b) cl d)

Fig. 3. A left-handed P-/3-hairpin (6) when viewed from above cannot be transformed into the coiled coil structures shown in (c)and (d). but can be coiled as shown in (a).

or @y&conformations. These P-P-corners can also be [15], 61-109 of ribonuclease S [16], and 41-77 of HIV-I considered as long right-handed P-P-hairpins bent in protease [12]. the middle. They are observed, for example, in regions, 163-183 of Streptomyces griseus protease A [17], 4. DISCUSSION 163-183 of cr-lytic protease [18], and 134-161 of bovine /?-trypsin [19]. An analysis of proteins of known structure shows Two &&corners can bc combined in a triple-strand that isolated P-P-hairpins or their isolated parts form, propeller-like structure as shown in Fig. 4d. Such struc- as a rule, coiled coil structures. Apparently, one of the tures are found in regions 63-105 of penicillopepsin reasons is that side chains in a twisted and coiled P-sheet

C N C N at bt ct d) Fig. 4 A schctuatic illustration of fl+corncrs. (a) A right-handed 0-p corner forlncd by a right-handed p-8 hairpin when vicwcd from the concave side. A straight line is an imaginary axis. (b) A prohibited Icft-handed &@-comer. (c) A prohibited &&corncr formed by a left-handed P-P-hairpln when vicwcd from the concave side, (d) A propcllcr-like structure of the three-stranded B-sheet which can bc considered as a combination of the two &&corncrs.

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are packed more compactly than in a flat one [3,20]. [Zl Nishikawa, K. and Scheraga, H.A. (1976) Macromolecules 9. Another reason is that the coiled coil structure is better 395-407. for interactions with water molecules than a flat p-p- 131 Salemme, F.R. and Weatherford, D.W. (1981) J. Mol. Biol. 146, 119-141. hairpin [21]. As considered above, coiling a P-&hairpin I41 Pauhng, L. and Corey, R.B. (1951) Proc. Nan. Acad. Sci. USA results in an increase of the short interchain Co-atom 37, 729-740. distances in the large hydrogen bonded rings that are PI Chothia. C. (1983) J. Moi. Biol. 163, 107-117. sterically favourable. 161 Deisenhofer, J. and Steigemann, W. (1975) Acta Cryst. B31, 238-250. Coiled coil structures are formed not only by double- I71 Holbrook, J.J., Liljas, A., Steindel, S.J. and Rossman, M.G. strand P-sheets. In proteins triple-strand and multiple- (1975) in: The Enzymes, vol. 11 (Boyer, P.D., ed.) pp. 191-292. strand P-sheets are often slightly coiled, especially their Academic Press, New York. edge B-strands and the ends of P-strands. It is of interest I81 Eklund, H., Samama, J.-P., Wallen, L., Brlnden, C.-l., that analysis of the observed cp, I,Ldistributions in pro- Akeson, A. and Jones, T.A. (1981) J. Mol. Biol. 146, 561-587. PI Finzel, B.C., Clancy, L.L., Holland, D.R., Muchmore, SW., teins distinguishes two subregions in the P-region, one Watenpaugh, K.D. and Einspahr, H.M. (1989) J. Mol. Biol. close to polyproline helix conformations and the other 209, 779-791 a close to the upper left corner [22]. As seen this is in good [lOI Efimov, A.V. (1986) Mol. Biol. (USSR) 20, 250-260. agreement with the alternation of cp, G values in coiled illI Cowan, SW., Newcomer, M.E. and Jones, T.A. (1990) Pro- teins: Structure, Function and Genetics 8, 44-61. P-sheets and, apparently, reflects the fact that coiled El21 Fitzgerald, P.M.D., McKeever, B&l., van Middlesworth, J.E., coil structures of P-sheets are rather widespread in pro- Springer, J.P., Heimbach, J.C., Leu, C.-T., Herber, W.K., Dix- teins. There is also a general tendency of the P-sheet on, R.A.F. and Darke, P.L. (1990) J. Biol. Chem. 265, residues included in the small hydrogen-bonding rings 14209-14219. to have more extended conformations than those in the 1131 Chothia. C. and Janin, J. (1982) Biochemistry 21, 3955-3965. iI41 Richardson, J.S., Getzoff, E.D. and Richardson, DC. (1978) large rings as a result of sterical interactions of side Proc. Natl. Acad. Sci. USA 75,2574-2578. chains. [151 James, M.N.G. and Sielecki, A.R. (1983) J. Mol. Biol. 163, Thus, the possibility of the polypeptidc chain to fold 299-361. into unique double-strand coiled coils and &&corners 1161 Wickoff, H.W., Tsernoglou, D., Hansen, A.W., Knox, J.R., Lee. B. and Richards, F.M. (1970) J. Biol. Chem. 245,305-328. is an important intrinsic property of the chain. The coil- 1171 Brayer, G.D., Delbaere, L.T.J. and James, M.N.G. (1978) J. ed coils and &&corners formed by &&hairpins with Mol. Biol. 124, 261-283. short loops are of particular value since there is a [I81 Brayer, G.D., Delbaere, J.T.J. and James, M.N.G. (1979) J. definite relationship between the structure and the Mol. Biol. 131, 743-775. amino acid sequence of such P-P-hairpins [23]. This 1191 Bartunik, H.D., Summers, L.J. and Bartsch, H.H. (1989) J. Mol. Biol. 210, 813-828. means that these structures can be predicted and the in- WI Efimov, A.V. (1977) Dokl. Akad. Nauk SSSR 235, 699-702. formation may be used in protein modelling and design. PII Kajava. A.V. and Lim, V.I. (1988) Biopolymers and Cell USSR) 4, 79-85. I221 L\dzhubei, A.A., Eisenmcnger, F., Tumanyan, V.G., Zinke, M., REFERENCES Brodzinski, S. and Esipovn, N.G. (1987) J. Biomol. Struct. Dynam. 5, 689-704. [I] Chothia, C. (1973) J. Mol. Biol. 75, 295-302. ~231 zfimov, A.V. (1987) FEBS Lett. 224, 372-376.

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