Key result
A systematic computational pipeline identified 75 rare cases of domain atrophy, demonstrating that protein domains can occasionally tolerate extreme mutations to form functional partial domains.
The study identifies 75 cases of domain atrophy, demonstrating that protein domains can rarely tolerate extreme mutations resulting in partial but functional domains.
Highlights domain resilience computationally; leaves open validation and cardiovascular protein applications.
BACKGROUND: Protein domains display a range of structural diversity, with numerous additions and deletions of secondary structural elements between related domains. We have observed a small number of cases of surprising large-scale deletions of core elements of structural domains. We propose a new concept called domain atrophy, where protein domains lose a significant number of core structural elements. RESULTS: Here, we implement a new pipeline to systematically identify new cases of domain atrophy across all known protein sequences. The output of this pipeline was carefully checked by hand, which filtered out partial domain instances that were unlikely to represent true domain atrophy due to misannotations or un-annotated sequence fragments. We identify 75 cases of domain atrophy, of which eight cases are found in a three-dimensional protein structure and 67 cases have been inferred based on mapping to a known homologous structure. Domains with structural variations include ancient folds such as the TIM-barrel and Rossmann folds. Most of these domains are observed to show structural loss that does not affect their functional sites. CONCLUSION: Our analysis has significantly increased the known cases of domain atrophy. We discuss specific instances of domain atrophy and see that there has often been a compensatory mechanism that helps to maintain the stability of the partial domain. Our study indicates that although domain atrophy is an extremely rare phenomenon, protein domains under certain circumstances can tolerate extreme mutations giving rise to partial, but functional, domains.
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Prakash et al. (2015) studied Protein domain atrophy (n=18,523,877). Domain atrophy vs. Complete protein domains was evaluated on Number of identified cases of domain atrophy. A systematic computational pipeline identified 75 rare cases of domain atrophy, demonstrating that protein domains can occasionally tolerate extreme mutations to form functional partial domains.
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