Question

We usually assume that closely related proteins (in terms of sequence and 3D structure) will have similar functions. On the other hand, some proteins can have similar functions and 3D structures without having very similar sequence. In other cases, proteins with different functions can have both similar primary and tertiary structures. Give an example of each case. Briefly explain how this can occur from an evolutionary point of view.

Answer 1

As we know that prediction of protein function from sequence & structure is a difficult problem, because of different functions of homologous proteins. Many methods of function prediction are based on identifying matched sequence and/or structure between a protein of unknown function and one or more well-understood proteins.

Other methods include inferring conservation patterns in members of a functionally uncharacterized family for which many sequences and structures are known. However, these inferences are tenuous. Such methods provide reasonable guesses at function, but are far from truth. It is therefore fortunate that the development of whole-organism approaches and comparative genomics permits other approaches to function prediction when the data are available. These include the use of protein–protein interaction patterns, and correlations between occurrences of related proteins in different organisms, as indicators of functional properties. Even if it is possible to ascribe a particular function to a gene product, the protein may have multiple functions. A fundamental problem is that function is in many cases an ill-defined concept.

Proteins of similarity in sequence are usually homologous and may have a similar function. Hence proteins in a newly sequenced genome are routinely annotated using the sequences of similar proteins in other genomes. However, closely related proteins may not always share the same function.For example, the yeast Gal1 and Gal3 proteins are paralogs (73% identity and 92% similarity) that have evolved very different functions with Gal1 being a galactokinase and Gal3 being a transcriptional inducer.There is no hard sequence-similarity threshold for "safe" function prediction; many proteins of barely detectable sequence similarity have the same function while others (such as Gal1 and Gal3) are highly similar but have evolved different functions.

Chymotrypsin and subtilisin are both proteinases. Although they have entirely different folding patterns, they share a common mechanism, including the catalytic triad Ser-His-Asp. They are an example of convergent evolution. The Ser-His-Asp triad also appears in other proteins, including lipases and a natural catalytic antibody. This and other examples show that it is not possible to reason that if two proteins have different folding patterns they must have different functions. similar sequences produce similar protein structures, with divergence in structure increasing progressively with the divergence in sequence.

Conversely, similar structures are often found with very different sequences. For instance, many proteins form TIM barrels with no easily detectable relationship between their sequences.

Similar sequences and structures sometimes produce proteins with similar functions, but exceptions abound.

Conversely, similar functions are often carried out by proteins with dissimilar structures; examples include the many different families of proteinases, sugar kinases, and lysyl-tRNA synthetases.

Phosphoglucose isomerase acts as a neuroleukin, cytokine and a differentiation mediator as a monomer in the extracellular space and as a dimer in the cell involved in glucose metabolism Lysozyme is an O-glycosyl hydrolase, but α-lactalbumin does not have this catalytic activity. Instead it regulates the substrate specificity of galactosyl transferase through its sugar binding site, which is common to both α-lactalbumin and lysozyme. Both the sugar binding site and catalytic residues have been retained by lysozyme during evolution, but in α-lactalbumin, the catalytic residues have changed and it is no longer an enzyme.

It Not so Well Understood because of possibly 1. Function are not well defined e.g., biochemical, biological, phenotypical 2. The PDB is biased – it does not have a balanced repertoire of functions and those functions are not well defined 3. There are a number of functional classifications eg EC, GO that have differing coverage and dept

1#Same Structure Different Function - Alpha/beta proteins characterized as different superfamilies.

2$Same Structure Different Function

1#	2$, Less than 15% sequence identity
1ymv	1ymv,cheY,signal transduction
1pdo	1pdo, Mannose Transporter
1fla	1fla, Flavodoxin Electron Transport