Abstract
The CRAL_TRIO protein domain, which is unique to the Sec14 protein superfamily, binds to a diverse set of small lipophilic ligands. Similar domains are found in a range of different proteins including neurofibromatosis type-1, a Ras GTPase-activating Protein (RasGAP) and Rho guanine nucleotide exchange factors (RhoGEFs). Proteins containing this structural protein domain exhibit a low sequence similarity and ligand specificity while maintaining an overall characteristic three-dimensional structure. We have previously demonstrated that the BNIP-2 and Cdc42GAP Homology (BCH) protein domain, which shares a low sequence homology with the CRAL_TRIO domain, can serve as a regulatory scaffold that binds to Rho, RhoGEFs and RhoGAPs to control various cell signalling processes. In this work, we investigate 175 BCH domain-containing proteins from a wide range of different organisms. A phylogenetic analysis with ∼100 CRAL_TRIO and similar domains from eight representative species indicates a clear distinction of BCH-containing proteins as a novel subclass within the CRAL_TRIO/Sec14 superfamily. BCH-containing proteins contain a hallmark sequence motif R(R/K)h(R/K)(R/K)NL(R/K)xhhhhHPs (‘h’ is large and hydrophobic residue and ‘s’ is small and weekly polar residue) and can be further subdivided into three unique subtypes associated with BNIP-2-N, macro- and RhoGAP-type protein domains. A previously unknown group of genes encoding ‘BCH-only’ domains is also identified in plants and arthropod species. Based on an analysis of their gene-structure and their protein domain context we hypothesize that BCH domain-containing genes evolved through gene duplication, intron insertions and domain swapping events. Furthermore, we explore the point of divergence between BCH and CRAL-TRIO proteins in relation to their ability to bind small GTPases, GAPs and GEFs and lipid ligands. Our study suggests a need for a more extensive analysis of previously uncharacterized BCH, ‘BCH-like’ and CRAL_TRIO-containing proteins and their significance in regulating signaling events involving small GTPases.
Highlights
The functional complexity of living organisms is reflected by the number of genes or their protein products, and by the cross-talk between them
We identified 98 proteins from eight representative organisms that belong to other subgroups within the Sec14 superfamily. These were aligned with the dataset of 175 BNIP-2 and Cdc42GAP Homology (BCH) domains, which based on their alignment with CRAL_TRIO domains were isolated from their full-length proteins
We show in this article that this extra N-terminal extension is essential for forming the complete three-dimensional BCH domain structure
Summary
The functional complexity of living organisms is reflected by the number of genes or their protein products, and by the cross-talk between them. This is signified by the fact that there are 1195 classes of known protein domain folds (based on latest release of Structural Classification of Proteins; SCOP database) belonging to 38221 Protein Data Bank entries of experimentally solved structures, indicating that multiple proteins tend to fold in a similar three dimensional structure. The ‘Sec superfamily’ is one such large superfamily of protein modules [1,2] The members of this gene family have the ability to bind multiple small hydrophobic molecules such as phosphatidylinositol (PI), tocopherol, retinaldehyde etc. The Sec14-protein (Sec14p) of yeast was the first identified member of this superfamily and is known to be involved in exchanging PI and phosphatidylcholine (PC) between lipid membrane bilayers, making it essential for the transport of secretory proteins from the Golgi complex [4]
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