Functional Equivalency Inferred from “Authoritative Sources” in Networks of Homologous Proteins

A one-on-one mapping of protein functionality across different species is a critical component of comparative analysis. This paper presents a heuristic algorithm for discovering the Most Likely Functional Counterparts (MoLFunCs) of a protein, based on simple concepts from network theory. A key feature of our algorithm is utilization of the user's knowledge to assign high confidence to selected functional identification. We show use of the algorithm to retrieve functional equivalents for 7 membrane proteins, from an exploration of almost 40 genomes form multiple online resources. We verify the functional equivalency of our dataset through a series of tests that include sequence, structure and function comparisons. Comparison is made to the OMA methodology, which also identifies one-on-one mapping between proteins from different species. Based on that comparison, we believe that incorporation of user's knowledge as a key aspect of the technique adds value to purely statistical formal methods.

[1]  E. Campbell,et al.  Crystal Structure of a Mammalian Voltage-Dependent Shaker Family K+ Channel , 2005, Science.

[2]  Tatiana Tatusova,et al.  NCBI Reference Sequence (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins , 2004, Nucleic Acids Res..

[3]  Jing Yao,et al.  Uncoupling Proton Activation of Vanilloid Receptor TRPV1 , 2007, The Journal of Neuroscience.

[4]  E. Azene,et al.  Pore-to-gate coupling of HCN channels revealed by a pore variant that contributes to gating but not permeation. , 2005, Biochemical and biophysical research communications.

[5]  L. Wollmuth,et al.  Structure and gating of the glutamate receptor ion channel , 2004, Trends in Neurosciences.

[6]  T. Bonnert,et al.  Functional characterisation of the S512Y mutant vanilloid human TRPV1 receptor , 2005, British journal of pharmacology.

[7]  C. Deutsch.  Potassium channel ontogeny. , 2002, Annual review of physiology.

[8]  C. Wahl-Schott,et al.  An Arginine Residue in the Pore Region Is a Key Determinant of Chloride Dependence in Cardiac Pacemaker Channels* , 2005, Journal of Biological Chemistry.

[9]  F. Cohen,et al.  Co-evolution of proteins with their interaction partners. , 2000, Journal of molecular biology.

[10]  Kyunglim Lee,et al.  Effects of mutation at a conserved N‐glycosylation site in the bovine retinal cyclic nucleotide‐gated ion channel , 2000, FEBS letters.

[11]  C. Stoeckert,et al.  OrthoMCL: identification of ortholog groups for eukaryotic genomes. , 2003, Genome research.

[12]  H. Guy,et al.  A common architecture for K+ channels and ionotropic glutamate receptors? , 2003, Trends in Neurosciences.

[13]  Y. Jan,et al.  Alteration of voltage-dependence of Shaker potassium channel by mutations in the S4 sequence , 1991, Nature.

[14]  L. Aravind,et al.  Identification of the prokaryotic ligand-gated ion channels and their implications for the mechanisms and origins of animal Cys-loop ion channels , 2004, Genome Biology.

[15]  Sean R. Eddy,et al.  Profile hidden Markov models , 1998, Bioinform..

[16]  Gabriel Moreno-Hagelsieb,et al.  Choosing BLAST options for better detection of orthologs as reciprocal best hits , 2008, Bioinform..

[17]  Charles Elkan,et al.  The Transporter Classification Database: recent advances , 2008, Nucleic Acids Res..

[18]  J. Thompson,et al.  CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. , 1994, Nucleic acids research.

[19]  Teresa M. Przytycka,et al.  COCO-CL: hierarchical clustering of homology relations based on evolutionary correlations , 2006, Bioinform..

[20]  A. Karschin,et al.  Stable cation coordination at a single outer pore residue defines permeation properties in Kir channels , 2000, FEBS letters.

[21]  A. Krogh,et al.  Predicting transmembrane protein topology with a hidden Markov model: application to complete genomes. , 2001, Journal of molecular biology.

[22]  T. Kuner,et al.  Glutamate receptor channel signatures. , 2001, Trends in pharmacological sciences.

[23]  Jun Chen,et al.  The S4–S5 linker couples voltage sensing and activation of pacemaker channels , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[24]  Robert C. Edgar,et al.  MUSCLE: multiple sequence alignment with high accuracy and high throughput. , 2004, Nucleic acids research.

[25]  Christian von Mering,et al.  eggNOG: automated construction and annotation of orthologous groups of genes , 2007, Nucleic Acids Res..

[26]  S. Herzig,et al.  A critical GxxxA motif in the γ6 calcium channel subunit mediates its inhibitory effect on Cav3.1 calcium current , 2008, The Journal of physiology.

[27]  J. Ludwig,et al.  Molecular determinants of a Ca2+‐binding site in the pore of cyclic nucleotide‐gated channels: S5/S6 segments control affinity of intrapore glutamates , 1999, The EMBO journal.

[28]  E. Koonin,et al.  Orthology, paralogy and proposed classification for paralog subtypes. , 2002, Trends in genetics : TIG.

[29]  W. N. Zagotta,et al.  Cyclic nucleotide-gated channels: shedding light on the opening of a channel pore , 2001, Nature Reviews Neuroscience.

[30]  E. Jakobsson,et al.  Sequence-function analysis of the K+-selective family of ion channels using a comprehensive alignment and the KcsA channel structure. , 2003, Biophysical journal.

[31]  Nikos Kyrpides,et al.  The Genomes On Line Database (GOLD) in 2007: status of genomic and metagenomic projects and their associated metadata , 2007, Nucleic Acids Res..

[32]  T. McDonald,et al.  Voltage-Gated Potassium Channels: Regulation by Accessory Subunits , 2006, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[33]  Stephen L. Johnson,et al.  Pigment Pattern in jaguar/obelix Zebrafish Is Caused by a Kir7.1 Mutation: Implications for the Regulation of Melanosome Movement , 2006, PLoS genetics.

[34]  R. MacKinnon,et al.  Identification of an external divalent cation-binding site in the pore of a cGMP-activated channel , 1993, Neuron.

[35]  I-Min A. Chen,et al.  The Genomes On Line Database (GOLD) in 2007: status of genomic and metagenomic projects and their associated metadata , 2007, Nucleic Acids Res..

[36]  O. Pongs,et al.  Shaker encodes a family of putative potassium channel proteins in the nervous system of Drosophila. , 1988, The EMBO journal.

[37]  M. Boyett,et al.  Molecular Basis of Ion Selectivity, Block, and Rectification of the Inward Rectifier Kir3.1/Kir3.4 K+ Channel , 2003, Journal of Biological Chemistry.

[38]  B. Hughes,et al.  Modulation of the Kir7.1 potassium channel by extracellular and intracellular pH. , 2008, American journal of physiology. Cell physiology.

[39]  Gaston H. Gonnet,et al.  OMA Browser - Exploring orthologous relations across 352 complete genomes , 2007, Bioinform..

[40]  C. Marshall,et al.  Evolution and structural diversification of hyperpolarization-activated cyclic nucleotide-gated channel genes. , 2007, Physiological genomics.

[41]  Gang Liu,et al.  Automatic clustering of orthologs and inparalogs shared by multiple proteomes , 2006, ISMB.

[42]  G. Pertea,et al.  Cross-referencing eukaryotic genomes: TIGR Orthologous Gene Alignments (TOGA). , 2002, Genome research.

[43]  D. Lipman,et al.  A genomic perspective on protein families. , 1997, Science.