642 Nature Vol. 274 17 August 1978 considerably improve on the speed and of the polypeptide chain) in ture, but it is only a special example of therefore the feasibility of trial and of known conformation. B. Robson the offen irregular bends and loops error testing of real problems-an at the University of Manchester which comprise a substantial fraction approach that is still necessary when and P. Chou and G. Fasman at of the surface of globular proteins. geophysical results can often be inter­ Brandeis University use these statistics Although these features are poorly preted by an infinity of possible models to determine the likely location of located by available treatments they of which the most geologically sensible the same structural features in are just the regions of chain most likely must then be sought. So far such an proteins of unknown 3-D structure. to be involved in intermolecular events. evaluation is still a human perogative, The other broad approach is intrinsi­ An improvement in the location of although one wonders for how much cally kinetic and is founded upon the these bends has been introduced re­ longer! Mussett and Dagley (Liver­ assumption that when proteins begin cently by Rose (Nature 272, 586; 1978). pool) showed how the volcanic activity to fold, local interactions (between When the free energies of transferring of Mull is now confined to within 3 nearby amino acids) predominate over each side chain from an million years some 60 million years interactions between amino acids more aqueous to a non-polar environment ago. Banks and Swain (Lancaster & distantly separated in linear sequence. are plotted as a function of linear Leicester) raised the problem of the Many workers have used this assump­ sequence, turns and loops appear as source of isostatic compensation, a tion as the basis for a predictive local minima, between maxima which problem of major importance since the method and V. Lim, of the USSR represent regions of the polypeptide inception of plate tectonics and there­ Academy of Sciences, has published a chain which form the hydrophobic pro­ fore the potentially great depths of the set of rules which allow the estimation tein core. This is a welcome adjunct to levels of isostatic compensation on the of the total folding _ of globular the current empirical prediction tech­ continents. Studies of the gravity field proteins. niques, since the algorithm described in East Africa now suggest that while Since none of these methods yet has a firm thermodynamic basis. the depth of compensation for ,the competes with crystallography in pre­ With the help of these methods plateau is unknown, the smaller struc­ cision of structure determination, their many potential sites of post-trans­ ture of the Kenya dome, on which the value to biochemists is restricted to lational modification, such as limited rif.t valleys lie, is compensated at fairly applications which only require ap­ or adenylylation, can be shallow depths, less than 55 km-such proximate structural information. A explored using existing amino acid results being consistent wi-th results good example of the use of the em­ sequence information. However, the from North America which indicate pirical approach is the independent correlation of acceptor sequences with that gravity anomalies of long wave­ estimation of secondary struc­ predicted structural features should be lengths, - 1,000 km or more, have ture for comparison with that deter­ made with some caution. One must perfect isostatic compensation, but mined by spectroscopic methods. first be satisfied that the modification wavelengths of less than 100 km are Regions of sequence which lack regular of interest occurs after the full tertiary only imperfectly compensa•ted. Rice structure can also be estimated and structures of the molecules are (Newcastle) questioned the standard these indicate likely sites for proteolytic acquired. For example, Linguppa et al. gravitational segregation model for attack. (Proc. natn. Acad. Sci. U.S.A. 75, the Skaergaard intrusive and provided This type of strategy has been 2338; 1978) show that the a convective alternative that appeared adopted by Beely (Biochem biophys. of a-lactalbumin only occurs during its equally adept at explaining volcanic Res. Commun. 76, 1051; 1977) and synthesis on the ribosome. Pless et al. differentiation or homogenising salad Aubert et al. (Arch. Biochem. Biophys. (Proc. natn. Acad. Sci. U.S.A. 74, 134; oil. D 175, 410; 1976) who find that sugar 1977) find that a variety of glyco­ chains seem to be preferentially at­ proteins can only serve as carbohydrate tached to glycoproteins at P-turns. acceptors if they are supplied to the Beely reports that 30 out of 31 glyco­ system in their denatured state. sylated residues occur in sequences The lack of structure during this par­ Turning points in favouring the /3-turn. He points out ticular modification obviously weakens that although the amino acid sequence the argument for a structural basis of predicted protein Asn (sugar)-X-Ser (or Thr) is a neces­ the observed specificity. With this pro­ sary condition for glycosylation, it is viso, the methods discussed here may structures not sufficient, and his analysis points well prove powerful in locating or con­ from M. Geisow to an additional conformational re­ firming potential sites of biochemical quirement. Carbohydrate is present at modification of globular proteins. D IN recent years, considerable improve­ /3-turns in the known structures of ments have been made in the accuracy human immunoglobulin heavy chain 100 years ago of protein conformation derived from and RNase B. Small et al. (Biochem. IT is stated in the French papers that amino acid sequence data alone. The biophys. Res. Commun. 79, 341; 1977) Mr. Edison is to have no reward what­ widespread adoption of this approach find that 80% of amino acids phos­ ever at the Paris Exhibition for his may be judged by the number of recent phorylated by protein kinases are also phonograph. The reasons alleged for reviews, including two from authors in located in sequences predicted to be in this apparent denial of justice are some­ what amusing. The jury of the class of laboratories specialising in the experi­ the /3-turn conformation. instruments of precision declared that mental determination of protein 3~D It may be that the respon­ the phonograph could not be con­ structure (Shulze Angew. Chem. 16, sible for these post-translational sidered as at all an instrument of pre­ 23; 1977, Sternberg & Thornton Nature modifications require a particular con­ cision, but merely a toy; consequently 271, 15; 1978). formation of their target amino acids, they sent it to the class of telegraphy to be rewarded. But the telegraphists In the most general terms, there are but an overriding consideration must replied that it was of no use whatever two empirical approaches to the esti­ be that such sequences are exposed at in telegraphy, and refused to examine mation of protein folding from the surfaces of their protein substrates. it. The consequence is that the most sequence information. The best known The /3-turn is certainly a surface struc- wonderful invention, .probably, in the Exhibition, will be passed by un­ of these uses the frequencies with which mentioned and unrewarded. particular amino acids occur in a-helix, M. Geisow is at the National Institute for From Nature /8, 15 August, 424; 1878. /3-structure or .B-turns (180 ° reversals Medical Research, London.

C Macmillan Journals Ltd 1978