ReviewEvolution of protein function, from a structural perspective
Introduction
Evolutionary relationships are often exploited to provide insights into the biological role of uncharacterised proteins. Properties are inferred on the basis that protein family members commonly exhibit some similarity in function. With the proliferation of sequence, structural and biochemical data in recent years, however, scientists have identified many remarkable examples of protein evolution: relatives sharing high structural, and even sequence similarity can perform disparate functions, and conversely, proteins having dissimilar structures can have identical biochemical roles. A complete understanding of these complexities at the molecular level requires detailed structural analyses, since function and three-dimensional structure are inherently linked.
These observations are exemplified by two well studied cases. Lysozyme and α-lactalbumin share high sequence and structural similarity, yet α-lactalbumin does not exhibit the O-glycosyl hydrolase activity of lysozyme, and instead regulates the substrate specificity of galactosyltransferase [1]. The sugar-binding site of α-lactalbumin has remained during evolution whilst the catalytic residues have changed. The classic example of functional convergence is that of subtilisin and chymotrypsin. They have different structural folds, yet they have the same Ser–His–Asp catalytic triad and both function as serine proteases via the same catalytic mechanism [2].
Evolutionary relationships are traditionally detected by sequence similarity, but structural comparison is a far more powerful method, since protein structure is conserved even after all trace of sequence similarity disappears. This observation, combined with the growth in the protein data bank (pdb) [3], has allowed biologists to classify proteins into structural evolutionary families 4, 5, many of which are now well populated. Individually, protein structures may provide details of binding, catalysis and signalling. Collectively, in the context of sequence information, structural relatives can reveal the underlying mechanisms of evolving new functions from a structural standpoint. Similarly, with the atomic comparison of functional analogues such as chymotrypsin and subtilisin one can identify the common structural motif to which their functional similarity can be attributed.
Here we discuss recent, novel fold/function analyses, and then focus on the various mechanisms of evolving new functions with reference to recent examples in the literature. The review centres on enzymes; nevertheless, many points raised are applicable to proteins in general.
Section snippets
Enzyme structure/function relationships
Recent analyses have provided insights into novel structure/function relationships, and have highlighted the functional versatility of protein structures within homologues families, folds and secondary structure classes. With few consistent descriptors for other functional types, emphasis is placed on enzymes as the hierarchical Enzyme Classification (EC) scheme [6] facilitates the systematic comparisons of enzyme function.
Mechanisms of functional evolution
Given the versatility of folds and functions, how is function modulated through gene structure, sequence and thus three-dimensional-structural changes? A simple schematic diagram of the possible routes to new functions is given in Figure 5.
Gene fusion
Given that there are a limited number of folds, probably a few thousand at most 9, 37, yet an immeasurable number of functions required to sustain life, modular construction has been an important mechanism for the evolution of new gene functions. This is illustrated by the high percentage (30%) of polypeptide chains within the pdb that comprise more than one domain [38], and this percentage represents a lower limit since for many proteins, the structure of only one domain of several has been
Gene recruitment
Gene recruitment refers to the acquisition of a new function by an existing gene. This evolutionary strategy is exemplified by the recruitment of enzymes as crystallins, the structural proteins in the eye lens [45]. These new roles were acquired by modifications in gene expression.
Following recruitment, multi-functional genes are subject to two or more selective pressures, resulting in constraints on adaptability. As noted by Piatigorsky and Wistow [46], such pressures can lead to one of three
Conclusions
An understanding of the biological role of all gene products is the principal objective of genome analysis. How these functions have evolved is also of major intellectual and scientific interest. At the molecular level, three-dimensional structures facilitate the detection of distant evolutionary relationships, which can reveal how function is modified during evolution by sequence and structural changes. Understanding this evolution of function will provide clues for the design of proteins with
Acknowledgements
Annabelle E Todd is supported by a BBSRC special studentship and is sponsored by Oxford Molecular. Christine A Orengo is supported by the Medical Research Council. We also acknowledge support from the Bloomsbury Structural Biology Centre.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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