Abstract 2900: Phylogenetic classification, structural evolution, and functional divergence of the Ras superfamily of GTPases as tracked by the Conserved Domain Database (CDD)..

Abstract

Abstract The Conserved Domain Database (CDD, http://www.ncbi.nlm.nih.gov/Structure/cdd/cdd.shtml) is part of NCBI's Entrez query and retrieval system and is a collection of annotated multiple sequence alignment (MSA) models representing ancient conserved protein domains, basic units of protein function and protein evolution.These MSA models are available as position specific score matrices (PSSMs) for fast identification of conserved domains in protein sequences via Reverse Position Specific -BLAST (RPS-BLAST), a variation of the commonly used PSI-BLAST. The domain models can be viewed and examined interactively using NCBI's CDTree/Cn3D software applications. Conserved functional annotations such as key catalytic and ligand-binding sites are displayed on protein structures sharing significant homology to the query, thereby inferring the underlying mechanism(s) of the protein domain family. Here, we present the current, functionally annotated, evolutionary classification of the Ras GTPase superfamily, including the circularly permuted Ras-like domain, and its downstream effectors such as RasGAP and RasGEF. Using CDTree/Cn3D tools, subfamilies in diverse organisms were inferred from the MSAs, phylogenetic trees, and domain architectures of the Ras superfamily. Furthermore, several subfamilies comprising of only uncharacterized protein sequences have their functions annotated by inference from the molecular and cellular functions of known related proteins having 3D structure, and based on the available literature. We demonstrate the utility of CDTree/Cn3D in studying molecular evolution of protein domain families, and in accelerating the pace of biological discovery by enabling researchers to obtain valuable clues regarding as-yet-unidentified molecular properties and mechanisms. CDTree/Cn3D software is freely available for download via the CDD website. Citation Format: James S. Song, Narmada Thanki, Myra K. Derbyshire, Marc Gwadz, Noreen R. Gonzales, Aron Marchler-Bauer, Stephen H. Bryant. Phylogenetic classification, structural evolution, and functional divergence of the Ras superfamily of GTPases as tracked by the Conserved Domain Database (CDD). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2900. doi:10.1158/1538-7445.AM2013-2900