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MAO: Multiple Alignment Ontology MAO Knowledge Base for System Biology http://www-igbmc.u-strasbg.fr/BioInfo/MAO/mao Organism classification, the ‘tree of life’ Lecompte O, Ripp R, Thierry JC, Moras D, Poch (2002) Comparative analysis of ribosomal proteins in complete genomes: an example of reductive evolution at the domain scale. Nucleic Acids Res. 24:5382-90. Phylogenetic studies Suga H, Katoh K, Miyata (2001) Sponge homologs of vertebrate protein tyrosine kinases and frequent domain shufflings in the early evolution of animals before the parazoan-eumetazoan split. Gene. 280:195-201. Protein family evolution Birck C, Damian L, Marty- Detraves C, Lougarre A, Schulze- Briese C, Koehl P, Fournier D, Paquereau L, Samama JP. (2004) A new lectin family with structure similarity to actinoporins revealed by the crystal structure of Xerocomus chrysenteron lectin XCL. J Mol Biol. 5:1409-20. Protein: structure comparison, modelli The 3D structure of a family of fungal lectins shows unexpected, significant structure similarity with actinoporins, a family of pore-forming toxins. Structure and sequence signatures suggest a potential sugar binding site in the lectin XCL and a possible evolutionary relationship. One member of this family, from X. chrysenteron, induces drastic changes in the actin cytoskeleton after sugar binding at the cell surface and has potent insecticidal activity. Sequence alignment of XCL with the 2 actinoporins of known structure. Secondary structure is indicated by coils (-helix) and arrows (-strand). Structural comparison of XCL (cyan) and sticholysin II (StnII) from Stichodactyla helianthus (purple). StnII shares high structural similarity with EqtII. Comparative genomics Brudno M, Do CB, Cooper GM, Kim MF, Davydov E, Green ED, Sidow A, Batzoglou S (2003) NISC Comparative Sequencing Program. LAGAN and Multi-LAGAN: efficient tools for large-scale multiple alignment of genomic DNA. Genome Res. 13:721-31. Visualization of a multiple genome alignment using VISTA. This plot shows the conservation between human and chimpanzee, cow, mouse, and fugu around the first intron of the cMet gene. Human gene Brachydanio rerio Drosophila… Yeast Other mammals Mouse / rat Primate s Modu le Transcription factor binding site Identification of well conserved regions in orthogolous sequences Potential transcription factor binding sites Sites or modules present in group of co- regulated genes Phylogenetic footprinting Gene: identification, validation Prediction of functional sites Bianchetti L, Thompson JD, Lecompte O, Plewniak F & Poch O . (2005) vALId: V alidation of protein sequence quality based on multiple ALI gnment d ata. JBCB. Sequence error detection Potential sequence errors are detected by multiple alignment analysis and verified where possible by comparison to EST sequences. Phylogenetic footprinting is a technique that identifies regulatory elements by finding well conserved regions in a set of orthologous non- coding DNA sequences from multiple species. Massire C, Jaeger L, Westhof E. (1998) Derivation of the three-dimensional architecture of bacterial ribonuclease P RNAs from comparative sequence analysis. J Mol Biol. 4:773-93. RNA: sequence, structure, function Part of a multiple alignment of 18 type B bacterial sequences. The secondary structure of bacterial RNase P RNA, a ribozyme responsible for the maturation of the 5′ end of tRNAs, based on sequence comparison analysis. RNase P RNA secondary structures fall into two types, A and B, which share a common core, but differ in their peripheral elements. CPK model of the B. subtilis RNase P RNA-tRNA complex Simplified 2D representations of (A) a typical type A sequence and of (B) a type B sequence with their characteristic tertiary interactions. A. B. Gangloff YG, Werten S, Romier C, Carre L, Poch O, Moras D, Davidson I. (2000) The human TFIID components TAF(II)135 and TAF(II)20 and the yeast SAGA components ADA1 and TAF(II)68 heterodimerize to form histone-like pairs. Mol Cell Biol. 20:340-51. Protein interaction networks Sequence comparison of the putative histone fold regions of hTAFII135, hTAFII105, dTAFII110, yADA1, and a putative S. pombe ADA1 Summary of the structures and some of the molecular interactions within the TFIID and SAGA complexes. It was shown, by two-hybrid analysis, that hTAFII20 heterodimerizes with hTAFII135. The interaction requires a domain of hTAFII135 which shows sequence homology to H2A and to the yeast SAGA component ADA1. These results are indicative of a histone fold type of interaction between hTAFII20-hTAFII135 and yTAFII68-yADA1, which therefore constitute novel histone-like pairs in the TFIID and SAGA complexes. TFIID ySAGA Therapeutics, drug discovery A multiple alignment of nuclear receptors highlights the conserved N-terminal DBD domain and a dispensable insertion domain in the N-terminal part of the LBD. Mutations (black arrows) in the VDR DBD prevent the receptor from activating gene transcription although 1,25-(OH)2D3 binding is normal. However, missense mutations in the LBD cause reduced or complete hormone insensitivity. As a result, vitamin D analogs have been developed that have the potential to interact with the receptor at amino acid contact points that differ from those utilized by the natural ligand and this alternative interaction can restore the function of mutant VDRs. Vitamin D is critically important for the development, growth, and maintenance of a healthy skeleton from birth until death. Mutations in the vitamin D receptor (VDR) gene lead to the early onset of severe rickets. Rochel N, Wurtz JM, Mitschler A, Klaholz B, Moras D. (2000) The crystal structure of the nuclear receptor for vitamin D bound to its natural ligand. Mol Cell. 5:173-9. Peter J. Malloy, J. Wesley Pike and David Feldman (1999) The Vitamin D Receptor and the Syndrome of Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets (1999). Endocrine Reviews 20 (2):156-188 Gardezi SA, Nguyen C, Malloy PJ, Posner GH, Feldman D, Peleg S. (2001) A rationale for treatment of hereditary vitamin D-resistant rickets with analogs of 1 alpha,25-dihydroxyvitamin D(3). J Biol Chem. 31:29148-56. VDR PXR THR AR DBD LBD Insertion Domain Multiple Alignment Ontology multiple_sequence_alignment sub_alignment alignment_column alignment_sequence sequence_feature residue amino_acid column_conservation nucleotide residue_function structural_location atom 3d_atomic_point sequence_feature_type is_attribute is_attribute is_attribute is_attribute part_of is_attribute is_attribute is_a part_of is_attribute is_attribute is_a is_a is_attribute part_of part_of is_attribute part_of part_of part_of accession An example of integrated analysis : the interleukin-1 protein family. Interleukin-1 (IL-1 ) is a proinflammatory cytokine produced by activated macrophages and monocytes. It functions in the generation of systemic and local responses to infection, injury, and immunological challenges and is the primary cause of chronic and acute inflammation (Dinarello, 1998 ). The IL-1 gene cluster on human chromosome 2q contains several related genes including the genes encoding IL-1A , IL-1B and their endogenous receptor antagonist IL-1RN. IL1A and IL1B are synthesised as larger precursors. The N terminal approx. 115 amino acids form a propeptide that is cleaved off to release the active interleukin-1. Both IL1A and IL1B bind to the same IL1-specific receptor on the target cell. Interleukin-1 Interleukin-1 propeptide IL1Fx IL1A IL1B IL1RN propept ide cleavag e exon 2exon 3 exon 4 exon 5 exon 6 exon 7 Ensembl:il1 a_human PDB:1itb_a Interpr o The IL1A propeptide produces apoptosis in malignant but not normal cell lines. It is subject to post-transcriptional modifications. It also includes a nuclear localisation signal (NLS) that is functional after cleavage. Within the nucleus, the IL1A propeptide may interact with elements of RNA processing affecting alternate splicing of genes involved in the regulation of apoptosis. (Pollock et al, 2003). Ontologies have become important in bioinformatics as they provide a structured representation of the knowledge available in a particular domain [1]. MAO is a task-oriented ontology for data retrieval and exchange in the fields of DNA/RNA alignment, protein sequence and protein structure alignment. The purpose of the MAO ontology is to standardise descriptions of alignments and the associated structural and functional information in order to allow the different alignment construction and analysis applications to communicate with each other. Most of the features associated with multiple alignments are defined as MAO concepts, ranging from a single residue to sub-families of sequences and/or 3D structures. Attributes are assigned to the concepts where appropriate, in order to permit the integration of more complex information such as residue function or activity, sequence feature conservation or 3D structural location. An important criterium in the design of MAO was the possibility to link with other biological ontologies, in particular those registered at the OBO (Open Biomedical Ontologies) web site. By providing an integrated environment for all the data available for a protein family, MAO facilitates knowledge extraction which can then be presented in a user-friendly format [2]. MAO can thus serve as a basis for a repository of annotated protein families, that will help in sharing information in the community. NLS RNA interaction myristoyla tion phosphorylati on mutation R>Q (SeattleSNPs) «damaging » (PPHpredict) mutation A>S (SeattleSNPs) «benign » (PPHpredict) cleavage IL1A reduces tumorigenicity* IL1B promotes invasiveness* *Differential effects of IL-1 on tumor development (Song et al, 2003) IIL1A propeptide processing and comparison with IL1B SCOR: hierarchical structural classification of RNA. Klosterman PS, Hendrix DK, Tamura M, Holbrook SR, Brenner SE. (2004) Three-dimensional motifs from the SCOR, structural classification of RNA database: extruded strands, base triples, tetraloops and U- turns. Nucleic Acids Res. 8:2342-52. SCOR: 1nbs:b:139-142,b:166-170 AAAA,GAGUA Loop with dinucleotide platform SCOR: 1nbs:b:147-150,b:159-161 UACG,UAU Loop with dinucleotide platform Protein: hierarchical function annotati Brelivet Y, Kammerer S, Rochel N, Poch O, Moras D . (2004) Signature of the oligomeric behaviour of nuclear receptors at the sequence and structural level. EMBO Rep. 5:423-9. Conserved motifs, residues Sequence analysis revealed two sets of differentially conserved residues, partitioning the Nuclear Receptor superfamily into two classes. Domain organisation Multiple alignments are used to identify protein domains, either ab initio or by searching databases of known domains, e.g. Pfam, Interpro, CDD... Sequence homolog detection Class I : homodimers Class II : heterodimers C..C GM LBD AB Vitamin D3 receptor VDR DBD Hinge C..C Multiple alignments improve protein homolog searches e.g. PSI-Blast, ProfileSearch, HMMER, SAM… E E H R a. b. c. a. Full length protein annotation b. Domain organisation c. Conserved motifs/residues Human genetics, SNPs Nicotine is the major addictive substance in cigarettes, and genes involved in sensing nicotine are logical candidates for vulnerability to nicotine addiction. Feng et al. studied 6 single-nucleotide polymorphisms (SNPs) in the CHRNA4 gene and 4 SNPs in the CHRNB2 gene in relation to nicotine dependence in a collection of 901 subjects (815 sibs and 86 parents) from 222 nuclear families with multiple nicotine-addicted sibs. They found 2 SNPs in exon 5 of the CHRNA4 gene to be significantly associated with a protective effect against nicotine addiction. (OMIM:118504) The pairwise |D | values for the six CHRNA4 SNPs were found to be quite high, which indicates that these six SNPs can be considered to be one haplotype block The six SNPs located on the CHRNA4 gene, showing their locations on the chromosome 20 genomic contig. SNP1 and SNP2 in exon 5 are synonymous SNPs revealed by direct DNA sequencing. Cross-species comparison of the DNA and protein sequences of a CHRNA4 coding segment (66 bp; 22 amino acids) in the cytoplasmic loop between transmembrane domains 3 and 4 Feng Y, Niu T, Xing H, Xu X, Chen C, Peng S, Wang L, Laird N, Xu X. (2004) A common haplotype of the nicotine acetylcholine receptor alpha 4 subunit gene is associated with vulnerability to nicotine addiction in men. Am J Hum Genet. 1:112-21. JD. Thompson, D. Moras, O. Poch, IGBMC, Illkirch, France. (julie,moras,poch)@igbmc SR. Holbrook, LBNL, Berkeley CA, USA. [email protected] K. Katoh, Bioinformatics Center, ICR, Kyoto, Japan. [email protected] P. Koehl, UC Davis, Davis, CA, USA. [email protected] E. Westhof, IBMC, Strasbourg, France. [email protected] Taxid (NCBI) biological_process (GO) cellular_component (GO) molecular_function (GO) protein_interactions (PSI) catalytic_site (CSA) RESID database Interpro External database OBO Ontology MAO concept SCOR is_a is_attribute pdb_name ndb_name is_attribute domain is_a [1] Bard, J.B. and Rhee, S.Y. 2004. Ontologies in biology: design, applications and future challenges. Nat Rev Genet. 3:213-222. [2] Lecompte, O., Thompson ,J.D., Plewniak, F., Thierry, J. and Poch O. 2001 Multiple alignment of complete sequences (MACS) in the post-genomic era. Gene 270:17-30. Iwabe N, Hara Y, Kumazawa Y, Shibamoto K, Saito Y, Miyata T, Katoh K (2004) Sister group relationship of turtles to the bird-crocodilian clade revealed by nuclear DNA-coded proteins. Mol Biol Evol. Dec 29.
