Proc. Natl. Acad. Sci. USA Vol. 93, pp.

14243–14248, December 1996 Colloquium Paper

This paper was presented at a colloquium entitled ‘‘Symmetries Throughout the Sciences,’’ organized by Ernest M. Henley, held May 11–12, 1996, at the National Academy of Sciences in Irvine, CA.

Symmetry, stability, and dynamics of multidomain and multicomponent protein systems


Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, United Kingdom

ABSTRACT Symmetry is commonly observed in many biological systems. Here we discuss representative examples of the role of symmetry in structural molecular biology. Point group symmetries are observed in many protein oligomers whose three-dimensional atomic structures have been elucidated by x-ray crystallography. Approximate symmetry also occurs in multidomain proteins. Symmetry often confers stability on the molecular system and results in economical usage of basic components to build the macromolecular structure. Symmetry is also associated with cooperativity. Mild perturbation from perfect symmetry may be essential in some systems for dynamic functions. Proteins are linear polymers of L-amino acids organized in a hierarchical way: amino acid sequence, helices and strands, structural motifs, globular domains, protomers, and oligomers (1, 2). At the lowest level of organization, the sequence of amino acids or primary structure is folded into -helices ( ), -strands ( ), and other secondary structures. These in turn usually form compact supersecondary structural motifs such as , , and , most of which are dependent on higherorder interactions for their stability. Thus, at the next level of organization globular domains may comprise several such motifs, stabilized by interactions between side chains of different amino acids known as tertiary interactions. Such domains usually fold independently, probably reflecting their evolutionary origins as smaller, independent proteins in earlier organisms. The individual gene products, the protomers or subunits, may contain several such globular domains in one polypeptide chain. At the highest level of organization, oligomers, which are assemblies of such protomers, often contain several different gene products, usually organized in a symmetrical way. Because L-amino acids are enantiomers, natural proteins synthesized from them on a ribosome cannot have mirror planes or centers of inversion. However, identical or similar protein motifs, globular domains, or protomers can be related by rotational symmetries. There are many examples of oligomers involving simple point group symmetries; Table 1 lists representative examples. Most common is 2-fold symmetry, which is found in many oligomers such as immunoglobulin, triose-phosphate isomerase, and wheat germ agglutinin. Threefold symmetry is also common; for example, it is found in bacteriochlorophyll protein and glucagon. Higher rotational symmetries are less common, although they do occur as shown in the pentraxin serum amyloid P-component (Fig. 1), which has nearly perfect 5-fold symmetry (11). Many oligomers with high rotational symmetry tend to be associated with a membrane or a surface coat of a cell or spherical virus. Alternatively, they may comprise a disc that is the basic building element of a tubular
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Table 1.

Representative proteins with rotational symmetry No. of subunits 2 2 4 3 3 4 4 5 5 Rotational symmetry Reference* 2 2 2 3 3 Three orthogonal 2-fold 4 5 5 3, 4 5 6 7 8 9 10 11, 12 13

Protein HIV proteinase B2 crystallin Immunoglobulins Purine nucleoside phosphorylase Porin Hemoglobin Neuraminidase Pentraxins -Subunit of types 1 and 2 heat-labile enterotoxins and cholera toxin Insulin Limulus C-reactive protein GroEL Aerolysin 20S proteosome Mandelate racemase Light-harvesting complex 2 GTP cyclohydrolase I trp RNA binding attenuating protein Aspartate transcarbamoylase Phaseolin Portal protein of bacteriophage Apoferritin Light-harvesting complex 1 Tobacco mosaic virus disc Coat of tomato bushy stunt virus

6 6 14 7 7 8 18 10 11 12 12 13 24 32 34 180

3- and 2-fold 6 7 7 7 8 9 5- and 2-fold 11 3- and 2-fold Tetramer of trimers 13 4-, 3-, and 2-fold 16 17 5-, 3-, and 2-fold

14, 15 16 17 18, 19 20 21 22 23 24 25 26 27 28 29 30 31

*Reference to crystal structure is provided if a crystal structure is available.

cytoskeletal protein or of a cylindrical virus; an example is the tobacco mosaic virus protein disc, which has 17-fold symmetry. Rotational operations are often combined together in oligomers with point group symmetry. Most common are point combinations of 2- and 3-fold symmetries, reflecting the formation of intermediate oligomers in assembly and or evolution rotational symmetries. Thus 222 symmetry is found in concanavalin A, and 32 symmetry is found in both aspartate
*To whom reprint requests should be addressed.


or solid structures. involving several hundred amino acids in a complicated but beautiful architecture. FIG. domains. as shown in Fig. and Stability For symmetry to play a role in any branch of science. This arises in biology from the enforced economies of living systems.and 3-fold symmetry. Thus. Thus. which occur in representations of this concept in Chinese and Japanese art. The zinc insulin hexamer. large systems such as viruses. the stability of the symmetrical resting or storage form of insulin is as vital to the organism as the instability or proteolytic sensitivity of the active protomeric form. as plane groups in arrays of bacteriochlorophyll protein and other membrane proteins. insulin in the cells of the endocrine pancreas. Each protomer is represented in a specific color. there must be multiple identical copies of certain objects. packaged as a hexamer comprising six copies of the insulin molecule and two zinc ions. Such structures are responsible for the highly structured but dynamic organization of the cell. 2. Symmetry. Sequence similarity with other proteins in the family shows that this structure is likely to be conserved (36) except in the evolutionarily oldest member. protomers are often related by line groups in fibrous structures such as microtubules and filamentous phage. Thus. Rotational symmetries may be combined with translations to form fibrous. such as serum amyloid P-component (Fig. 1. Pentraxins. as shorter chains with single point errors can be discarded more easily. ‘‘Symmetry signifies rest and binding. which have a half-life of only a few minutes. Higher levels of organization.’’ Life is often defined as motion. harmony.and 3-fold symmetries. USA 93 (1996) transcarbamoylase and the zinc insulin hexamer shown in Fig. Crystal structure of pentameric human serum amyloid P-component (11) showing 5-fold symmetry. But they are also relevant to the fast-growing field of structural molecular biology. surface planar. and flagella are usually constructed from multiple copies of the same protein. a living organism is the very antithesis of ‘‘rest and binding. of course. Thus. the protein FIG. Nevertheless. units are more or less identical. if they lasted longer the sensitivity of the regulation by the hormone would be lost. which is concerned principally with symmetry and structure at the level of whole organisms and the cell. which has perfect 3-fold and approximate 2-fold symmetries (14. the pancreas. The structure of the zinc insulin hexamer as defined by Hodgkin and coworkers (14). It is fascinating that this example of yin and yang in biology involves a molecule with both 2. asymmetry motion and loosening. Sci. such as tomato bushy stunt virus. from Limulus polyphemus . Of course. Acad. DNA. This form is thermodynamically stable and resistant to proteolytic degradation. written of the visual arts. Economy. 1) (11) and C-reactive protein (12). each of the units may be extremely complex. generally. We describe examples of exact or approximate symmetry that relate supersecondary structural motifs. and as space groups in crystalline storage granules— for example. Making many smaller copies is also a safer strategy. may equally well be used of nature. or whole proteins in complex multidomain proteins or oligomers. in these cases iron and nucleic acid. give rise to hollow shells that can be used to package molecules safely. than constructing it from a single protein chain. such as octahedral 432 symmetry found in ferritin and icosahedral 532 symmetry found in many spherical viruses.14244 Colloquium Paper: Blundell and Srinivasan Proc. In this article we focus on point group symmetries.’’ These words. that in certain respects life requires rest and binding. 15). They were reflected by D’Arcy Thompson in his classic work On Growth and Form (40). 2. The hexamer is viewed down the exact 3-fold axis (triangle at the center). cell-cytoskeleta. When it is released into circulation it dissociates quickly into protomers. as the system would be turned on for too long. the lowest energy state of an assembly is a symmetrical one. 39). and stability. Why then should symmetry be found in life at the molecular level? Will it not be selectively disadvantageous in evolution? The answer is. and. In general. have pentameric ring structures. In humans the hormone may ‘‘rest’’ for several days in the endocrine gland. Natl. is a good example. Building a molecular structure from several small identical proteins requires less genetic material. the arrows indicate positions of approximate 2-fold axes relating pairs of protomers. multienzyme complexes. This is of particular importance as the three nucleic acid bases that code for one building unit (one amino acid) of a protein involve about five times as many atoms as the amino acid itself. and the zinc at the center is shown in red. 2. which has both 2. economy of mass may be the reason why many proteins that encircle DNA are hexamers (37) and many proteins of viral coats that completely encapsulate nucleic acids are icosahedral structures of 60 or more subunits (38.

especially in bronze mirrors that display both rotational and mirror symmetries and reflect the search for permanent. Acad. Alzheimer disease. In a similar way ‘‘Rangoli’’ patterns.(2 and 222). A fine example of this symmetrical architecture is found in the design of the Chartres Cathedral. serum amyloid Pcomponent occurs in many amyloid diseases such as amyloidosis. Most of these are stable molecules. Thus. each combarrel structures. and Creutzfeld–Jacob disease. in the coral tree. the -subunit of heterotrimeric G proteins (50–52). are almost always cyclic. . By maintaining the symmetry of the tetramer. harmony. Natl. the lectin glycosylation site interferes with the classical legume lectin dimer interface. Symmetry and Cooperativity Symmetry-related subunits or domains in protein structures often communicate among themselves. peanut lectin (34). These molecules have 2. For example. where it binds tightly to the amyloid fibers. In fact. where the addition of oxygen molecules increases the affinity for others. When they become denatured. The hexameric Limulus C-reactive protein (Limulus CRP) structure has been generated on the basis of sequence similarity with serum amyloid P-component (36). While 30% of the oxygen from free oxygen concentration of 130 M in lungs can be transferred to tissues by an oligomeric globin. also led to symmetry in its visual arts and architecture. The three-dimensional structure (45) is arranged as two ‘‘domains’’ each containing two motifs related by 2-fold symmetry. although the mechanism is still not fully understood (55–57). these proteins have evolved to be very stable. In the transition between the two states it is known that the spatial disposition of the subunits undergoes dramatic changes. 5-. An inner cylinder of parallel -strands is surrounded by an outer cylinder of -helices. which need to survive during the acute-phase response in the circulation. 46). resulting in highly stable ‘‘rings’’ (48). symmetrical relationships expressed in Confucian philosophy and taken as necessary for the stability of Chinese feudal society. Quaternary structures of proteins with the lectin fold. although. as they must last for the lifetime of the individual. an increasing problem as humans live longer than they did when they were under the selective pressure of evolution! Similar proteins (47) are secreted onto the surface of some bacterial spores to increase their survival in a hostile environment. in triose-phosphate isomerase and many related -motifs. Because the lens must remain transparent when it loses its nucleus. but this is particularly true of the pentraxins. 4. or more blades. one on each subunit. and 6-fold symmetries (42). cataracts are more likely to form. there are many examples in plants as well as animals. the oxygen molecules are efficiently picked up in the lungs and deposited in the tissues. Symmetry axes are indicated for each structure. reminiscent of the structures of oligomers. and human serum amyloid P-component (11). and increases their resistance to removal by the body’s defense system (44). jack bean concanavalin A (35). The seminal work of Perutz (54) on hemoglobin defined the molecular mechanism. decorates them. The relationship of Jesus and the twelve apostles has given rise to many circular church windows with pseudo 3. Very interesting pseudosymmetries. The crystal structures used are pea lectin (32). FIG. In a similar manner. Such molecules are known as lectins. The two symmetry-related Greek-key motifs within a domain are shown in two different colors and are related by approximate 2-fold axes (arrows). Christianity. This was first discovered by Haurowitz (53) for hemoglobin. the oxygen affinity is optimally controlled. 3. Sci. Neuraminidase (10). made of -strands that are related by approximate rotational symmetry. and peace. USA 93 (1996) 14245 multichain oligomers. once established. the -crystallins of the vertebrate eye lens are composed of a polypeptide chain that has been internally quadruplicated in evolution so that a similar motif occurs four times in series. Thus. This suggests that cyclic pentameric or hexameric arrangements may be important for the biological functions of pentraxins (41). pentraxins need several equivalent binding sites. Internal symmetry in B-crystallin (45. bovine S-lectin (33). eight. the oxy (relaxed or R-state) and deoxy (tense or T-state) states. and so its ability to make new proteins. thereby signifying a stable state. affinity is first suppressed but then sharply increased as the concentration of oxygen increases to that found in the lungs. can also relate protein domains and motifs. the two domains are themselves related by a further approximate 2-fold symmetry as shown in Fig. 3. it is a textbook example in which the four subunits retain approximate 222 symmetry but exist in two forms. The crystallins are further assembled into complex Proc. which probably involve binding or linking several polysaccharidecontaining cells or molecules together to form a stable multicomponent system. eight supersecondary prising an -helix folded onto a -strand. Thus. Symmetry operations that relate supersecondary structural motifs within globular domains can also lead to cyclic packing of identical or similar units. which establish a mood of restfulness and permanence. used in India as a form of worshipping Hindu gods. Arrows represent 2-fold axes in the plane of the paper. as shown in Fig.and 4-fold symmetries. are circularly arranged (49). the two domains are related by an approximate 2-fold axis. and several other proteins are constructed as propellers with seven. which is hexameric (16). resulting in an unusual dimer (43). they show cooperativity. To achieve this. Such harmonious and symmetrical motifs occur widely in Chinese art. less than 20% would be transferred by a hemoglobin with only one subunit.Colloquium Paper: Blundell and Srinivasan (horseshoe crab). 4. if the cooperativity between the subunits of hemoglobin FIG. producing an aesthetically pleasing structure.

respectively. 60). USA 93 (1996) were absent.. offer a pseudosymmetry. angiotensinogen. 5 a with b) is a pseudosymmetrical (2-fold axis) molecule in which the two topologically equivalent catalytic groups (the two ‘‘hands’’ of the molecule) are now in distinctly different environments. reflected in rearrangements within the subunits and a 7 rotation between subunits. In humans the design is manifested as pepsin to digest food. are good examples. The fructose ATP reaction catalyzed by this enzyme appears to involve cooperativity. which have an approximate 2-fold axis shown as an arrow. it has to package all its own nucleic acid within its capsid. Major structural rearrangements are observed in many oligomers that show cooperativity.6-bisphosphatase (19 ) (57. 60 for a review). 5a). A pronounced rearrangement of tertiary structure is also observed in the aspartate transcarbamoylase. while the other can pull more effectively. (a and b) Comparison of monomeric pepsin (a) with two symmetry-related lobes (61) and dimeric HIV proteinase (b) (4) inspired by the analyses of Blundell and coworkers (61–63). Fig. have evolved from a protein made of two identical copies of a smaller molecule. where the organism has to travel light.’’ God and Adam. the biological catalysts that endow dynamic properties on living organisms. Comparison of the R-state and T-state of the enzyme reveals a remarkable 12 rotation of the catalytic trimer and 15 rotation of the regulatory dimer resulting in an 11-Å separation of the subunit surfaces (see ref. For example. and as renin to process a key hormone precursor. evolution has accepted mutations in aspartic proteinases that have modified the details of each half while keeping the basic architecture (or tertiary structure) of the ancestral protein. The enzyme consists of six copies of each of a catalytic and a regulatory polypeptide chain. which is composed of two discs of 7-fold symmetric subunits (17) and . one can push. Sci. Each subunit is composed of two domains. as cathepsin D to process proteins within cells. 4). 5b shows the symmetrical structure of the HIV proteinase (3. The net result (compare Fig. i. related by three orthogonal 2-fold symmetry axes (222 symmetry). which are themselves related by symmetry (59). which include the digestive enzyme pepsin (Fig. Such retroviral proteinases are not efficient enzymes. each in human form. (c) The two topologically equivalent catalytic groups (the ‘‘hands’’ Asp-32 and Asp-215 of pepsin). Acad. 5. There is an analogy here with the loss of symmetry in Michelangelo’s ‘‘Creation. and plants. mammals. 5c) and so inhibit maturation of the virus (see ref. which is involved in the formation of carbamoyl aspartate from the carbamoyl phosphate and aspartate. 64 for a review). the aspartic proteinases. It is now evident that such enzymes still exist in retroviruses. All show positive cooperativity in ligand binding. 66) have shown that GroEL. In all these cases symmetry is central to biological function. which controls blood pressure. which is now found in fungi. Symmetry thus plays a key role in the molecular regulation of important physiological processes. X-ray analyses have defined the structures of R-states and T-states for four proteins in addition to hemoglobin. resulting in a highly symmetric 32 structure. Saibil and coworkers (65. configuration related by a mirror plane—the right hand of God ref lected as the left hand of Adam. medicinal chemists have exploited their symmetry to make symmetrical drugs that bind more tightly than the substrate at the catalytic site (Fig. As described above phosphofructokinases are generally tetramers of identical polypeptide chains. glycogen phosphorylase (10 ). Changes between symmetry-related subunits and their angle of rotation between subunits for the other three proteins are as follows: hemoglobin (15 ). Indeed. their hands touch in a FIG. Symmetry and Motion But what of motion at the molecular level? Does nature abandon symmetry or does it distort symmetrical structures so that they reach a point of disequilibrium with resulting motion? Is there a parallel with Mao Tse Tung’s dialectical reinterpretation of Confucian relationships where the thesis and antithesis are no longer in balance (as in yin and yang). and a new synthesis takes place? Enzymes.e. and fructose-1. In the meantime.14246 Colloquium Paper: Blundell and Srinivasan Proc. The arrows indicate the positions of approximate and perfect 2-fold axes relating domains (pepsin) and protomers (HIV proteinase). Michelangelo disturbed the symmetry gently but firmly to make it clear that the relationship is loosened and life f lows strongly from God into Adam. They are now used as part of a cocktail of HIV antivirals that are beginning to have success in the clinic. A much better enzyme results. Natl. less oxygen would be transported from the lungs to the tissues (58).

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