Length Variations amongst Protein Domain Superfamilies and Consequences on Structure and Function

Background: Related 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. Methodology: In 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 o