Conformational diversity and protein evolution – a 60-year-old hypothesis revisited

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Abstract

Complex organisms have evolved from a limited number of primordial genes and proteins. However, the mechanisms by which the earliest proteins evolved and then served as the origin for the present diversity of protein function are unknown. Here, we outline a hypothesis based on the ‘new view’ of proteins whereby one sequence can adopt multiple structures and functions. We suggest that such conformational diversity could increase the functional diversity of a limited repertoire of sequences and, thereby, facilitate the evolution of new proteins and functions from old ones.

Section snippets

The ‘new view’ of protein function

Traditionally, it is assumed that a given sequence dictates a single 3D structure upon which function is entirely dependent. This view is manifested in the ‘lock-and-key’ and ‘induced-fit’ models of action, in which the structure is entirely fixed or changes (locally, around the active site) only after a ligand is bound (Box 1). Both models are strongly supported by the principal method used to study protein structure – X-ray crystallography. However, crystallization is, by definition, a

Linking conformational diversity and functional diversity

An intriguing consequence of conformational diversity is that it provides a mechanism for functional diversity at the single-protein level. A protein that adopts several different conformations could, in principle, exert several different functions [20]. A significant number of proteins that exhibit multiple activities have been identified 21, 22 but the mechanism behind this promiscuity or cross-reactivity, in most cases, involves the same active-site configuration that confers the original

Conformational diversity and protein evolution

In the 1930s, Landsteiner and Pauling 44, 45 proposed that proteins (antibodies in this case) can exist as an ensemble of isomers with different structures but with similar free energy. They realized that if each isomer was capable of binding to a different ligand, then functional diversity could go far beyond sequence diversity (Box 2). This idea, although considered outlandish for many decades, now proves to be remarkably prescient of the ‘new view’ of proteins. It also has intriguing

The co-evolution of fold and function

The proposed model (Box 3) describes how existing genes could diverge to evolve new functions, but it can also be extended to explain how primordial protein precursors evolved in the first place. The emergence of the first functional proteins is a complete mystery. It is generally assumed that proteins exert function only when folded into a well-defined 3D structure. However, fold alone provides no selective advantage and, thus, cannot evolve independently. We are therefore left with an

Concluding remarks

The ‘new view’ of proteins has prompted the revision of many facets of protein science. Here, we have outlined the intriguing implications that this ‘new view’ might have for protein evolution. The hypotheses described are supported by many properties of today's proteins, including the recent demonstration of a linkage between conformational diversity and multi-specificity in antibodies [16] (Fig. 2). Moreover, although present-day enzymes do not necessarily retain the activities of their

Acknowledgements

Financial support by the Wellcome Trust, the EU (through the ENDIRPRO network) and the Israel Science Foundation is gratefully acknowledged.

Glossary

Glossary

  
Numerous terms exist that describe the ability of a single protein to exhibit more than one specificity or perform more than one function. These terms are not necessarily distinct and are, in many senses, overlapping; they are often used in parallel or in a different context than described herein. Here, we attempt to define a clearer terminology and distinct uses for these terms. A detailed discussion of promiscuity, moonlighting and cross-reactivity can be found in Ref. [22].
Conformational

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