Origin and evolution of the cystic fibrosis transmembrane regulator protein R domain

• Type of Material: Article
• Authors: Aswathy Sebastian, Georgia Institute of Technology; Lavanya Rishishwar, Georgia Institute of Technology; Jianrong Wang, Georgia Institute of Technology; Karen F. Bernard, Emory University; Andrew B. Conley, Georgia Institute of Technology; Nael McCarty, Emory University; I. King Jordan, Georgia Institute of Technology
• Language: English
• Date: 2013-07-10
• Publisher: Springer Verlag (Germany)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 Elsevier B.V.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.gene.2013.02.050
• Title of Journal or Parent Work: Генетика / Genetika / Russian Journal of Genetics
• ISSN: 0016-6758
• Volume: 523
• Issue: 2
• Start Page: 137
• End Page: 146
• Keywords: Coding sequence; PHOSPHORYLATION SITES; SEQUENCE; Neo-functionalization; Life Sciences & Biomedicine; GENES; DIVERGENCE; Molecular evolution; SPLICED EXONS; Genetics & Heredity; ACTIVATION; Cystic fibrosis; R domain; CONDUCTANCE REGULATOR; ABC; Science & Technology; IDENTIFICATION; CFTR CHLORIDE CHANNEL
• Research Categories: Biology, Genetics

Abstract

The Cystic Fibrosis Transmembrane Conductance Regulator protein (CFTR) is a member of the ABC transporter superfamily. CFTR is distinguished from all other members of this superfamily by its status as an ion channel as well as the presence of its unique regulatory (R) domain. We investigated the origin and subsequent evolution of the R domain along the CFTR evolutionary lineage. The R domain protein coding sequence originated via the loss of a splice donor site at the 3' end of exon 14, leading to the subsequent read-through and capture of formerly intronic sequence as novel coding sequence. Inclusion of the remaining part of the R domain coding sequence in the CFTR transcript involved a lineage-specific gain of exonic sequence with no homology to protein coding sequences outside of CFTR and loss of two exons conserved among ABC family members. These events occurred at the base of the Gnathostome evolutionary lineage ~. 550-650. million years ago. The apparent origination of the R domain de novo from previously non-coding sequence is consistent with its lack of sequence similarity to other domains as well as its intrinsically disordered structure, which has important implications for its function. In particular, this lack of structure may provide for a dynamic and inducible regulatory activity based on transient physical interactions with more structured domains of the protein. Since its acquisition along the CFTR evolutionary lineage, the R domain has evolved more rapidly than any other CFTR domain; however, there is no evidence for positive (adaptive) selection in the evolution of the domain. The R domain does show a distinct pattern of relative evolutionary rates compared to other CFTR domains, which sheds additional light on the connection between its function and evolution. The regulatory function of the R domain is dependent upon a fairly small number of sites that are subject to phosphorylation, and these sites were fixed very early in R domain evolution and have remained largely invariant since that time. In contrast, the rest of the R domain has been free to drift in sequence space leading to a more star-like phylogeny than seen for the other CFTR domains. The case of the R domain suggests that domain acquisition via the de novo creation of coding sequence, and the novel functional utility that such an event would seemingly entail, can be one route by which neo-functionalization is favored to occur.