Deciphering the cause of evolutionary variance within intrinsically disordered regions in human proteins

Abstract

Why the intrinsically disordered regions evolve within human proteome has became an interesting question for a decade. Till date, it remains an unsolved yet an intriguing issue to investigate why some of the disordered regions evolve rapidly while the rest are highly conserved across mammalian species. Identifying the key biological factors, responsible for the variation in the conservation rate of different disordered regions within the human proteome, may revisit the above issue. We emphasized that among the other biological features (multifunctionality, gene essentiality, protein connectivity, number of unique domains, gene expression level and expression breadth) considered in our study, the number of unique protein domains acts as a strong determinant that negatively influences the conservation of disordered regions. In this context, we justified that proteins having a fewer types of domains preferably need to conserve their disordered regions to enhance their structural flexibility which in turn will facilitate their molecular interactions. In contrast, the selection pressure acting on the stretches of disordered regions is not so strong in the case of multi-domains proteins. Therefore, we reasoned that the presence of conserved disordered stretches may compensate the functions of multiple domains within a single domain protein. Interestingly, we noticed that the influence of the unique domain number and expression level acts differently on the evolution of disordered regions from that of well-structured ones.

Keywords:

• conservation score
• protein domain
• selection pressure
• unstructured
• protein folding

Acknowledgments

The authors are thankful to Bin Xue for helping in the prediction of the intrinsic disorder using the PONDR-FIT server. The authors gratefully acknowledge David Alvarez-Ponce, Assistant Professor, Department of Biology, University of Nevada, Reno, USA for his critical reading of the manuscript. The authors are thankful to the Anonymous Reviewers for their valuable suggestions that have helped us to improve the quality of the manuscript.