A protein superfamily is the largest grouping (
clade) of
proteins for which
common ancestry can be inferred (see
homology). Usually this common ancestry is inferred from
structural alignment[1] and mechanistic similarity, even if no sequence similarity is evident.[2]Sequence homology can then be deduced even if not apparent (due to low sequence similarity). Superfamilies typically contain several
protein families which show sequence similarity within each family. The term protein clan is commonly used for
protease and
glycosyl hydrolases superfamilies based on the
MEROPS and
CAZy classification systems.[2][3]
Identification
Above,
secondary structural conservation of 80 members of the
PA protease clan (superfamily). H indicates
α-helix, E indicates
β-sheet, L indicates loop. Below, sequence conservation for the same alignment. Arrows indicate
catalytic triad residues. Aligned on the basis of structure by
DALI
Superfamilies of proteins are identified using a number of methods. Closely related members can be identified by different methods to those needed to group the most evolutionarily divergent members.
Historically, the similarity of different amino acid sequences has been the most common method of inferring
homology.[5] Sequence similarity is considered a good predictor of relatedness, since similar sequences are more likely the result of
gene duplication and
divergent evolution, rather than the result of
convergent evolution. Amino acid sequence is typically more conserved than DNA sequence (due to the
degenerate genetic code), so it is a more sensitive detection method. Since some of the amino acids have similar properties (e.g., charge, hydrophobicity, size),
conservative mutations that interchange them are often
neutral to function. The most conserved sequence regions of a protein often correspond to functionally important regions like
catalytic sites and binding sites, since these regions are less tolerant to sequence changes.
Using sequence similarity to infer homology has several limitations. There is no minimum level of sequence similarity guaranteed to produce identical structures. Over long periods of evolution, related proteins may show no detectable sequence similarity to one another. Sequences with many
insertions and deletions can also sometimes be difficult to
align and so identify the homologous sequence regions. In the
PA clan of
proteases, for example, not a single residue is conserved through the superfamily, not even those in the
catalytic triad. Conversely, the individual families that make up a superfamily are defined on the basis of their sequence alignment, for example the C04 protease family within the PA clan.
Nevertheless, sequence similarity is the most commonly used form of evidence to infer relatedness, since the number of known sequences vastly outnumbers the number of known
tertiary structures.[6] In the absence of structural information, sequence similarity constrains the limits of which proteins can be assigned to a superfamily.[6]
Structure is much more evolutionarily conserved than sequence, such that proteins with highly similar structures can have entirely different sequences.[7] Over very long evolutionary timescales, very few residues show detectable amino acid sequence conservation, however
secondary structural elements and
tertiary structural motifs are highly conserved. Some
protein dynamics[8] and
conformational changes of the protein structure may also be conserved, as is seen in the
serpin superfamily.[9] Consequently, protein tertiary structure can be used to detect homology between proteins even when no evidence of relatedness remains in their sequences.
Structural alignment programs, such as
DALI, use the 3D structure of a protein of interest to find proteins with similar folds.[10] However, on rare occasions, related proteins may evolve to be structurally dissimilar[11] and relatedness can only be inferred by other methods.[12][13][14]
The
catalytic mechanism of enzymes within a superfamily is commonly conserved, although
substrate specificity may be significantly different.[15] Catalytic residues also tend to occur in the same order in the protein sequence.[16] For the families within the PA clan of proteases, although there has been divergent evolution of the
catalytic triad residues used to perform catalysis, all members use a similar mechanism to perform
covalent, nucleophilic catalysis on proteins, peptides or amino acids.[17] However, mechanism alone is not sufficient to infer relatedness. Some catalytic mechanisms have been
convergently evolved multiple times independently, and so form separate superfamilies,[18][19][20] and in some superfamilies display a range of different (though often chemically similar) mechanisms.[15][21]
Evolutionary significance
Protein superfamilies represent the current limits of our ability to identify common ancestry.[22] They are the largest
evolutionary grouping based on direct
evidence that is currently possible. They are therefore amongst the most ancient evolutionary events currently studied. Some superfamilies have members present in all
kingdoms of
life, indicating that the last common ancestor of that superfamily was in the
last universal common ancestor of all life (LUCA).[23]
Superfamily members may be in different species, with the ancestral protein being the form of the protein that existed in the ancestral species (
orthology). Conversely, the proteins may be in the same species, but evolved from a single protein whose gene was
duplicated in the genome (
paralogy).
Diversification
A majority of proteins contain multiple domains. Between 66-80% of eukaryotic proteins have multiple domains while about 40-60% of prokaryotic proteins have multiple domains.[5] Over time, many of the superfamilies of domains have mixed together. In fact, it is very rare to find “consistently isolated superfamilies”.[5][1] When domains do combine, the N- to C-terminal domain order (the "domain architecture") is typically well conserved. Additionally, the number of domain combinations seen in nature is small compared to the number of possibilities, suggesting that selection acts on all combinations.[5]
Members share a sandwich-like structure of two
sheets of antiparallel
β strands (
Ig-fold), and are involved in recognition, binding, and
adhesion.[30][31]
Members share a large α8β8 barrel structure. It is one of the most common
protein folds and the
monophylicity of this superfamily is still contested.[35][36]
Protein superfamily resources
Several
biological databases document protein superfamilies and protein folds, for example:
Pfam - Protein families database of alignments and HMMs
PROSITE - Database of protein domains, families and functional sites
^Li D, Zhang L, Yin H, Xu H, Satkoski Trask J, Smith DG, Li Y, Yang M, Zhu Q (June 2014). "Evolution of primate α and θ defensins revealed by analysis of genomes". Molecular Biology Reports. 41 (6): 3859–66.
doi:
10.1007/s11033-014-3253-z.
PMID24557891.
S2CID14936647.
^
abDessailly, Benoit H.; Dawson, Natalie L.; Das, Sayoni; Orengo, Christine A. (2017), "Function Diversity within Folds and Superfamilies", From Protein Structure to Function with Bioinformatics, Springer Netherlands, pp. 295–325,
doi:
10.1007/978-94-024-1069-3_9,
ISBN9789402410679
^Nardini M, Dijkstra BW (December 1999). "Alpha/beta hydrolase fold enzymes: the family keeps growing". Current Opinion in Structural Biology. 9 (6): 732–7.
doi:
10.1016/S0959-440X(99)00037-8.
PMID10607665.
^Nagano N, Orengo CA, Thornton JM (August 2002). "One fold with many functions: the evolutionary relationships between TIM barrel families based on their sequences, structures and functions". Journal of Molecular Biology. 321 (5): 741–65.
doi:
10.1016/s0022-2836(02)00649-6.
PMID12206759.
^Farber G (1993). "An α/β-barrel full of evolutionary trouble". Current Opinion in Structural Biology. 3 (3): 409–412.
doi:
10.1016/S0959-440X(05)80114-9.