Internal symmetry in protein structures: prevalence, functional relevance and evolution☆
Introduction
Symmetry was one of the first recognized features of protein structures that were determined at atomic detail in three-dimensions (3-D) [1, 2]. With the accumulation of such structural data, it has become clear that symmetry in protein structures is not uncommon, and has been suggested to be relevant for folding, function and evolution of proteins [3, 4, 5, 6, 7•, 8, 9, 10]. Symmetry in protein structures is found at various levels of biological organization: whole biological assemblies, the quaternary association of proteins, within individual proteins and even within protein domains (Figure 1a). Analyses of quaternary associations in protein structures have led to the elucidation of various principles that underlie the symmetry of biologically relevant oligomeric states [11, 12, 13, 14, 15, 16].
Presence of symmetry in proteins at the level of tertiary structures or domains, termed internal symmetry, was first recognized through the examination of homologous amino acid sequence repeat stretches in proteins [17, 18]. Subsequently it became evident with the determination of numerous crystal structures of proteins that internal symmetry also exists in 3D, independent of sequence identity [19, 20]. The hierarchical classification of protein structures organized in databases such as SCOP and CATH [21, 22] has allowed the recognition of structural symmetry being widespread, from individual domains to domain folds (e.g. Ferredoxin-like, all forms of β-propellers, β-barrels, alpha toroids). Computational methods that utilize both sequence and structural information to systematically identify symmetry in protein structures have been developed over many years, which include COSEC2, DAVROS, OPAAS, Swelfe, RQA, GANG-STA+, SymD and CE-Symm (see Myers-Turnbull et al. [23••] for further details). Attempts to elucidate evolutionary models on a selected set of symmetric protein domains such as β-trefoils and β-propellers have been successful [7•, 24]. This inspired the design of symmetric protein structures with a potential for various applications [25, 26, 27]. Particularly in the last five years, there has been significant progress in identifying protein structural symmetry and describing its relevance to functions and evolution of proteins, which will be the primary focus below.
Section snippets
Recent computational methods to systematically identify protein internal symmetry
Recently developed computational methods to identify symmetry in protein structures include SymD and CE-Symm, which are amenable to large-scale applications [23••, 28••]. These encode complementary procedures that align a given protein structure to itself through systematic circular permutations while excluding diagonal matches, that is, self-matches. SymD relies on the residue level alignment of protein structures and employs an alignment scan procedure for each circular permutation of a
Symmetry can correlate with function
According to the conserved architecture model for the evolution of protein internal symmetry, symmetry in a tertiary protein structure resembles its ancestral oligomeric state (see below). Hence, it is possible that some of those ancestral oligomeric states indeed possessed functional ‘collaboration’ between ancestors of extant symmetric units within tertiary structures [38]. Such ‘collaborations’ could have been retained in the extant symmetric units. In the case of enzymatic activities that
Proposed models for the evolution of internal symmetry
Two prominent models for the evolution of internal symmetry in protein monomers are: (1) the conserved architecture model, in which an extant protein domain is likely to conserve the nature of symmetry from its ancestral quaternary association to its tertiary form and (2) the emergent architecture model, which posits that symmetry in an extant protein domain has emerged independently of its ancestral quaternary association. Both of these models rely on duplication and fusion events resulting
Outlook and scope
The exploration of internal symmetry in proteins is likely to yield as fascinating outcomes as the exploration of symmetry in quaternary structures. Unlike the case of quaternary structure, general principles for protein internal symmetry are poorly understood. Comparative analysis of evolutionarily related structures with internal symmetry is a challenge, especially if there has been extensive divergence between them, as it is non-trivial to determine equivalent domains or units. However, a
Conflict of interest statement
I declare that to the best of my knowledge I have no conflict of interest.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgments
I acknowledge the Medical Research Council, UK (U105185859). I thank M. Madan Babu, S. Chavali, T. Flock, A. Morgunov and N. Latysheva for their scientific inputs and comments on the manuscript.
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2020, Current Opinion in Structural BiologyCitation Excerpt :Early statistical projections already predicted only a small number of protein folds to be found in nature [4–6], hence suggesting the presence of a limit in the structural diversity of natural proteins. Redundancy in protein folds derives primarily from mechanisms that govern protein evolution such as duplication and recombination, which in turn are the main cause for the common occurrence of symmetry, pseudo-symmetry and domain duplications observable in protein architectures [7–9]. Non-natural protein folds, in contrast, represent an ensemble of structures estimated to largely exceed the number of natural folds [10,11].
MemSTATS: A Benchmark Set of Membrane Protein Symmetries and Pseudosymmetries
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2018, Current Opinion in Structural BiologyCitation Excerpt :In a string of publications from the 1970s and 1980s, Andrew McLachlan established gene duplication as a dominant phenomenon in the evolution of proteins and described the origin of many folds by repetition of simpler fragments [18,19]. Since then, the role of repetition has been substantiated further by numerous computational and experimental studies [20–25,26••,27••,28••]. The evolution of several prominent folds has been explored experimentally over the last 15 years and here, almost all the recapitulated scenarios involved the repetition of supersecondary structure elements.
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Glossary: This review focuses on internal symmetry at the level of tertiary structures and domains in proteins. Internal symmetry as defined here is independent of sequence identity, accommodates minor deviations from perfect symmetry and could also be termed as ‘pseudo symmetry’. The terms ‘symmetry’ and ‘pseudo symmetry’ in the context of protein tertiary structure or domain refer to internal symmetry in protein structures.