Superfamily of proteins

Sequence Homology

Members of the superfamily of proteins belonging to different families usually do not show any significant or easily detectable homology of amino acid sequences, nevertheless having similar secondary and tertiary structures and often possessing some kind of functional similarity. Often it is almost impossible or at least very difficult to align them with amino acid sequences, due to frequently observed insertions and deletions . For example, in the PA protease superfamily, no amino acid residue is conserved throughout the superfamily, including even those amino acid residues that make up the catalytic triads of these proteins.

Conversely, members of individual families that make up the superfamily are determined precisely by the principle of homology of amino acid sequences (primary structures) of proteins that make up the family. For example, in the PA protease superfamily there is a family of C04 proteases.

Structural homology

The secondary and tertiary structures of proteins that directly affect their functionality (for example, the ability of a receptor to recognize ligands — agonists and antagonists , or the ability of an enzyme to catalyze certain chemical reactions ) are much more evolutionarily conservative than the amino acid sequence. An example of this is the PA protease superfamily. In it, very few amino acid residues of proteins exhibit a significant degree of evolutionary conservatism, while the characteristic elements of the secondary structure, as well as their spatial ordering in tertiary structures, are very highly conservative.

Structural alignment and alignment programs, such as the DALI program, can use the three-dimensional secondary and tertiary structures of the proteins of interest to the researcher with the available database of protein structures in order to find proteins with similar folding . A comparison of three-dimensional secondary and tertiary structures of proteins helps to identify many cases of evolutionarily related (having a common evolutionary ancestor) proteins, the similarity of which would not be revealed by a simple analysis and comparison of their primary structures (amino acid sequences).

Mechanism and functional similarities

The catalytic mechanism of enzymes that are members of the superfamily is usually more or less conservative on the scale of the entire superfamily, however, their substrate specificity can vary significantly on the scale of the superfamily. As a result, the final functional purpose of proteins in the body can significantly vary, depending on what their substrate specificity is. That is, there may not be any external functional similarity.

Also (though not necessarily and not always) the catalytic domain of enzymes that are members of the superfamily tends to a high degree of conservatism of the amino acid sequence within this particular domain (and even more so - the secondary and tertiary structure of the catalytic domain). However, even if the amino acid sequence of the catalytic domain is not preserved, the catalytic mechanism itself and / or the secondary and tertiary structures of the catalytic domain can be preserved.

An example of the above conservation of the catalytic mechanism on the scale of the superfamily is, again, the PA protease superfamily. It contains proteins of very different final functional purpose (that is, there is no external functional similarity) - among them there is the digestive enzyme chymotrypsin , thrombolytic enzyme - plasminogen activator , toxins of bacteria and snakes and viral proteases that ensure the assembly of viral particles. As mentioned above, not a single amino acid residue is evolutionarily conserved on the scale of this superfamily, even in the catalytic domain. Nevertheless, all members of the superfamily have significant similarities between the specific catalytic elements of their three-dimensional structures. Moreover, although members of different PA protease superfamily families use different nucleophiles , they all produce covalent nucleophilic catalytic proteolysis of proteins or peptides by a common catalytic mechanism.

Superfamilies of proteins reflect the limitations of our current ability to identify a common ancestor ^[3] . Superfamily of proteins is the largest evolutionarily significant association of similar proteins and genes that can be done at the moment, based on direct evidence of similarity (in the case of superfamilies - mainly structural, and partly by mechanism). Therefore, the discovery of three-dimensional structural similarities of functionally and amino acid different proteins in living creatures that are very far away on the evolutionary ladder is one of the proofs of very ancient (possibly the most ancient among the generally studied) evolutionary events.

Some protein superfamilies contain proteins that are present in one form or another in all living creatures studied (for example, potassium channels ) in all kingdoms (including animals , plants , fungi , bacteria, and other prokaryotes ). This may indicate that the common ancestor of the proteins of these superfamilies was the proteins present in the universal common ancestor of all living beings ^[4] .

Superfamily members can be found in different species of animals, plants, unicellular creatures ( orthologous proteins). Moreover, the most evolutionarily ancient are, obviously, those members of the superfamily who belong to beings located at the very lowest steps of the evolutionary ladder. The common ancestor for these proteins, obviously, is the protein of some ancient extinct creature, which was a common ancestor for all those species in which proteins representing the superfamily are found. Thus, the study of orthologous proteins within the superfamilies of proteins can allow more accurate drawing of the species evolution tree.

In addition, several different representatives of a certain superfamily of proteins (including those performing different functions) can be found in the same organism of an animal, plant, or unicellular creature of the same species. Such proteins are called paralogous . These paralogous proteins can also come from one common protein ancestor, which at some stage of evolution was duplicated in the genome of this species. The study of paralogous proteins, their similarities and differences, helps to shed light on the path of the functional evolution of proteins.

• The PA protease superfamily is the chymotrypsin-like protease superfamily. Superfamily members have a similar structure in the form of a double β-barrel and similar proteolysis mechanisms, however, the degree of amino acid sequence homology is less than 10%. The superfamily contains both cysteine and serine proteases (that is, it uses different nucleophiles ). However, family members have a similar catalytic mechanism and a similar three-dimensional spatial structure of the catalytic domain. ^{[2] [5]}

• Superfamily α / β hydrolases . Members of the superfamily contain a similar structure in the form of an α / β-sheet containing 8 β-strands connected by α-helices , while the amino acid residues of the catalytic domain of all members of the superfamily are in the same place in the same order ^{[6 ]} although among the members of the superfamily there are proteases, lipases , peroxidases, esterases , epoxide hydrolases and dehalogenases. ^[7]

• Superfamily of Ras-like proteins. Superfamily members share a common catalytic G domain.

• Superfamily of TIM-barrels. Superfamily members have a common large α ₈ β ₈ barrel-shaped structure. This is one of the most common foldings among proteins, and therefore the legality of combining them all into one family (the monophilicity of these proteins) is still disputed. ^{[8] [9]}

• Superfamily of alkaline phosphatases . Superfamily members have a common structure resembling an αβα-sandwich, ^[10] and in addition, they catalyze common phosphatase reactions by a common mechanism. ^[eleven]

Several biological databases document protein superfamilies, in particular:

• Pfam
• PROSITE
• Interpro
• Pass2
• SUPERFAMILY
• SCOP and CATH

• Homology (biology)