Post 60: Why some proteins can perform more functions than others? 🤔

So far, we know about ~8,400 enzymatic functions, and only a handful of proteins can perform hundreds of functions, while others can only do a few.

One of the most beloved proteins among proteinologists is the TIM barrel, as its folding shape accommodates a wide variety of amino acids quite well. In fact, because the TIM barrel is more “designable,” it is often used when designing new functions through protein engineering. In contrast, other proteins, such as dihydrofolate reductase, can only perform a single function.

So why does this happen? The answer lies in the organization of the protein structure. “Polarity” is a property related to how catalytic residues are organized in relation to the residues that provide the protein’s body. If the residues in the active site are well separated from the residues that form the body, we refer to that as a high-polarity protein.

In proteins with low polarity, there is a more pronounced co-evolution between the active site residues and the body residues, which limits their ability to mutate over time; for a residue to mutate, others must also change. In contrast, in high-polarity proteins, catalytic residues can mutate more easily because they are less coupled to the body, often found in flexible loops, which likely allowed for the exploration of a greater variety of functions throughout evolution.

Refs:

• What makes a protein fold amenable to functional innovation? Fold polarity and stability trade-offs
• The 8,400 enzymatic functions

Note: Text originally published on 08/21/2024.