Abstract
BackgroundRelated protein domains of a superfamily can be specified by proteins of diverse lengths. The structural and functional implications of indels in a domain scaffold have been examined.MethodologyIn this study, domain superfamilies with large length variations (more than 30% difference from average domain size, referred as ‘length-deviant’ superfamilies and ‘length-rigid’ domain superfamilies (<10% length difference from average domain size) were analyzed for the functional impact of such structural differences. Our delineated dataset, derived from an objective algorithm, enables us to address indel roles in the presence of peculiar structural repeats, functional variation, protein-protein interactions and to examine ‘domain contexts’ of proteins tolerant to large length variations. Amongst the top-10 length-deviant superfamilies analyzed, we found that 80% of length-deviant superfamilies possess distant internal structural repeats and nearly half of them acquired diverse biological functions. In general, length-deviant superfamilies have higher chance, than length-rigid superfamilies, to be engaged in internal structural repeats. We also found that ∼40% of length-deviant domains exist as multi-domain proteins involving interactions with domains from the same or other superfamilies. Indels, in diverse domain superfamilies, were found to participate in the accretion of structural and functional features amongst related domains. With specific examples, we discuss how indels are involved directly or indirectly in the generation of oligomerization interfaces, introduction of substrate specificity, regulation of protein function and stability.ConclusionsOur data suggests a multitude of roles for indels that are specialized for domain members of different domain superfamilies. These specialist roles that we observe and trends in the extent of length variation could influence decision making in modeling of new superfamily members. Likewise, the observed limits of length variation, specific for each domain superfamily would be particularly relevant in the choice of alignment length search filters commonly applied in protein sequence analysis.
Highlights
During evolution, protein domains undergo many modifications in sequence and structure to achieve versatility in function
The observed limits of length variation, specific for each domain superfamily would be relevant in the choice of alignment length search filters commonly applied in protein sequence analysis
It was observed that for domain superfamilies with at least 4 members, 20% of the domains showed over 30% length variation from the mean domain size
Summary
Protein domains undergo many modifications in sequence and structure to achieve versatility in function. Diverse factors, such as the accumulation of sequence changes, gene duplications, gene combinations etc., are seen to contribute extensively to this diversity [1,2,3,4,5,6]. Hierarchical assemblies of protein structures in databanks such as SCOP [9] and CATH [10] only emphasize the diversity of proteins sharing similar structures and the tolerance of stable folds to variation in sequence and in domain lengths. Functional versatility is attributed to novel interfaces resulting from domain recombination and the mixing and modulation of pre-existing scaffolds through length modifications. The structural and functional implications of indels in a domain scaffold have been examined
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