Abstract
Analysis of structural variation in domain superfamilies can reveal constraints in protein evolution which aids protein structure prediction and classification. Structure-based sequence alignment of distantly related proteins, organized in PASS2 database, provides clues about structurally conserved regions among different functional families. Some superfamily members show large structural differences which are functionally relevant. This paper analyses the impact of structural divergence on function for multi-member superfamilies, selected from the PASS2 superfamily alignment database. Functional annotations within superfamilies, with structural outliers or ‘rebels’, are discussed in the context of structural variations. Overall, these data reinforce the idea that functional similarities cannot be extrapolated from mere structural conservation. The implication for fold-function prediction is that the functional annotations can only be inherited with very careful consideration, especially at low sequence identities.
Highlights
The availability of protein three-dimensional structures repeatedly confirms that a limited number of folds are shared by large number of protein sequences
Deviant Members of PASS2 Here, we emphasize that using an appropriate structure alignment protocol even on protein domains with low sequence identity, one can identify structural differences which occur due to a functional reason
These 159 superfamilies are characterized as single, two and multiple-outlier superfamilies (Figure S1). 41 superfamilies from the category of single and two outlier superfamilies are highly interesting, since they retain outliers which are family-specific in nature suggesting a functional context
Summary
The availability of protein three-dimensional structures repeatedly confirms that a limited number of folds are shared by large number of protein sequences. This limitation is imposed by the physical chemistry of the polypeptide [1,2,3]. It is quite uncommon to discover a new fold, while it is possible to observe a subtle conformational difference arising from some very common structural motifs [7]. The presence of such structural differences can be attributed to various reasons such as addition/deletion, circular permutation, strand inversion or withdrawal and b-hairpin flip/swap [8]. A difference in Enzyme Commission (E.C.) number [17] is reflected by either subtle or obvious differences in function
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