Protein Structure Vs. Function

It is a fundamental axiom of biology that the three-dimensional structure of a protein determines its function. But predicting function from structure is, in general, even harder than the prediction of structure from sequence. This is because a biologically useful definition of the function of a protein requires a description at several different levels. To the biochemist, function means the biochemical role of an individual protein: if it is an enzyme, function refers to the reaction catalyzed; if it is a signaling protein, function refers to the interactions that the protein makes. To the geneticist or cell biologist, function includes these roles but will also encompass the cellular roles of the protein, such as the phenotype of its deletion, the pathway in which it operates, among others. A physiologist or developmental biologist may have an even broader view of function, including tissue specificity and expression during the life cycle of the organism.

For example, consider the protein PTEN, an enzyme that is deleted or mutated in a high percentage of breast, brain, prostate and skin cancers. Its biochemical function is to hydrolyze phosphate from lipid and protein substrates (Figure 2-0.1a). One of its cellular functions is to regulate the level of phosphatidylinositol-3,4,5-trisphosphate (PIP3). In this capacity it serves as a negative regulator of the antiapoptotic, oncogenic kinase Akt/PKB (Figure 2-0.1b). For that reason it is also an important human tumor suppressor. It is essential for normal embryonic development in mice. And it helps set the life span of cells in the nematode worm C. elegans.

Which of these is its function? Obviously, all of them. Equally obviously, deducing all of them from only the sequence or even the structure of PTEN is extremely difficult.

An even more complex example is tubulin, which not only has several cellular functions, but also has more than one biochemical function: it is an enzyme that hydrolyzes GTP, and also a structural protein that polymerizes to form stiff hollow tubes (Figure 2-0.2a-b). In the cell, it forms a network of microtubules growing out of the centrosome (Figure 2-0.2e), creating a system of tracks along which proteins, vesicles and organelles can be moved from one part of the cell to another. In a dividing cell it forms the mitotic spindle that segregates the chromosomes equally into the two daughter cells. In certain motile eukaryotic cells it forms the cilia and flagella that provide propulsion or sweep fluid over the cell surface (Figure 2-0.2d).

Physiologically, it is the target for the antitumor drug taxol and the docking site for the motor proteins kinesin and dynein (Figure 2-0.2c). Tubulin is a protein whose functions cannot be condensed into a single sentence. This is likely to be the case for most gene products, especially in higher organisms.

Not surprisingly, biochemical function is generally the easiest to deduce from sequence and structure, although in some cases it is possible to go further. In the age of genomics, function will be derived in a partly empirical way from many different techniques employed together, augmented by comparative sequence analysis across genomes and the recognition of functional motifs in both the primary and tertiary structure. We shall illustrate in the next chapter how this operates in some selected cases. In this chapter, we outline the general principles that have been deduced about the relationship of structure to the biochemical function of gene products, focusing chiefly on binding, catalysis, and other biochemical functions of proteins and the ways in which these processes are controlled.