Marc Robinson-Rechavi Dpartement d'Ecologie et d'Evolution Universit de Lausanne Genomique structurale comparative et evolution des proteines What is structural genomics? Structural genomics with a phylogenetic framework: evolution of thermostability in T. maritima Some perspectives Lesley et al PNAS 99: La gnomique structurale c'est quoi ? Determination of the 3D structure of many proteins (all of one organism? all folds?) differences with "traditional" structural biology: the structure may be the first information concerning this protein deliberate effort to sample a large diversity of proteins target status public in TargetDB automatation differences with other "omics" : numbers still low ( structures / center / year) high quality of data example : pipeline of the Joint Center for Structural Genomics Taxonomic distribution of structural genomic results Arches Eucaryotes Figures de Todd et al 2005 J Mol Biol 348: Bactries Novelty distribution of structural genomics (SG) or "classical" (2yr-PDB) structures really new 0Identical or near-identical (95% seq. identity) 1Close sequence homologue detectable by SSEARCH 2Distant sequence homologue detectable by HMMs 3Distant homologue, where the relationship was detectable only from structure 4New superfamily belonging to an old fold 5New fold Structural genomics with a phylogenetic framework: Evolution of thermostability in T. maritima T. maritima: Bacteria, Thermotogales growth temperature = 80C model of structural genomics: highest success rate of crystalization How do proteins function at 80C? previous studies on structures: constrasted results: "There is more than one way to kill a cat" importance of salt bridges debate on compactness Few experimental structures No phylogenetic framework HAM1 homolog RMSD = 2.25 E. coli : 37C T. maritima : 80C Structural Genomics of Thermotoga maritima Proteins Shows that Contact Order Is a Major Determinant of Protein Thermostability M Robinson-Rechavi, A Godzik Structure 13: (2005) Contribution of Electrostatic Interactions, Compactness and Quaternary Structure to Protein Thermostability: Lessons from Structural Genomics of Thermotoga maritima M Robinson-Rechavi, A Alibs, A Godzik J Mol Biol 356: (2006) Materials and Methods BlastP PDB T. maritima against Hogenom protein families including PDB entries phylogeny (PhyML, JTT+ ) manual definition of homology relations definition of pairs: 1 T. maritima PDB entry per family 1 mesophilic bacterial PDB entry per family: - orthologs prefered over paralogs - smallest RMSD prefered when choice - xenologs (HGT) excluded structural analysis on single chains without HET atoms programs used: FATCAT, WHATIF, CaPTURE, DSSP, PQS, PSQS, contactOrder.pl FFAS search for distant homologs no structure in data network analysis: residues = nodes link if 4.5 apart in structure > 3 aa apart in sequence the differences between paralogs and between orthologs are in the same direction the differences between paralogs are larger -> differences due to T. maritima, not (other) change of function -> paralogs are more structurally divergent than orthologs (RMSD = 2.13 vs ) difference predicted by litterature, but significance marginal difference predicted by litterature, but no difference more electrostatic interactions in T. maritima (values per residue) more compact proteins in T. maritima Different proteins adapt to thermostability in different ways correlations between variations in contact order accessible surface area (ASA) connectivity protein length proportion of disorganized regions correlations between variations in salt bridges cation- interactions charged vs. polar (CvP) compositional bias conserved T. maritima - mesophile no change in ASA no correlation of contact order change with ASA change nor connectivity change high change in salt bridges strong correlation salt bridge - cation- variation different between T. maritima and mesophile high change in ASA correlation of contact order change with ASA change and connectivity change low change in salt bridges no correlation salt bridge - cation- variations quaternary structure no correlation Control: Are the differences between T. maritima and mesophilic bacteria really due to thermophily? no feature is significantly different between T. maritima and other thermophiles T. maritima protein structures are representative of thermophiles 0.5 Q98QL9_Mycoplasma_pulmonis_Bacteria SR54_MYCPN_Mycoplasma_pneumoniae_Bacteria SR54_MYCGE_Mycoplasma_genitalium_Bacteria Q9PR53_Ureaplasma_parvum_Bacteria Q8EWF3_Mycoplasma_penetrans_Bacteria Q8R9X0_Thermoanaerobacter_tengcongensis_Bacteria Q895M4_Clostridium_tetani_Bacteria Q97I98_Clostridium_acetobutylicum_Bacteria Q8XJP3_Clostridium_perfringens_Bacteria Q8CPH8_Staphylococcus_epidermidis_Bacteria Q99UN3_Staphylococcus_aureus_Bacteria Q8NX07_Staphylococcus_aureus_Bacteria Q92AK7_Listeria_innocua_Bacteria Q8Y695_Listeria_monocytogenes_Bacteria SR54_BACSU_Bacillus_subtilis_Bacteria AAP27711_Bacillus_anthracis_Bacteria AAP10765_Bacillus_cereus_Bacteria Q8ER02_Oceanobacillus_iheyensis_Bacteria Q9KA10_Bacillus_halodurans_Bacteria Q88WJ6_Lactobacillus_plantarum_Bacteria Q9CF65_Lactococcus_lactis_Bacteria Q99ZK1_Streptococcus_pyogenes_Bacteria Q8K7E7_Streptococcus_pyogenes_Bacteria Q8E5L2_Streptococcus_agalactiae_Bacteria 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SR54_HUMAN_Homo_sapiens_Eukaryota_1MFQ SR54_ACIAM_Acidianus_ambivalens_Archaea_1J8M SR54_SULSO_Sulfolobus_solfataricus_Archaea_1QZW FTSY_THEAQ_Thermus_aquaticus_Bacteria_1OKK FTSY_ECOLI_Escherichia_coli_Bacteria_1FTS example of cell division protein FtsY Different proteins adapt to thermostability in different ways (even homologs) 0.5 Q98QL9_Mycoplasma_pulmonis_Bacteria SR54_MYCPN_Mycoplasma_pneumoniae_Bacteria SR54_MYCGE_Mycoplasma_genitalium_Bacteria Q9PR53_Ureaplasma_parvum_Bacteria Q8EWF3_Mycoplasma_penetrans_Bacteria Q8R9X0_Thermoanaerobacter_tengcongensis_Bacteria Q895M4_Clostridium_tetani_Bacteria Q97I98_Clostridium_acetobutylicum_Bacteria Q8XJP3_Clostridium_perfringens_Bacteria Q8CPH8_Staphylococcus_epidermidis_Bacteria Q99UN3_Staphylococcus_aureus_Bacteria Q8NX07_Staphylococcus_aureus_Bacteria Q92AK7_Listeria_innocua_Bacteria Q8Y695_Listeria_monocytogenes_Bacteria SR54_BACSU_Bacillus_subtilis_Bacteria AAP27711_Bacillus_anthracis_Bacteria AAP10765_Bacillus_cereus_Bacteria 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SR54_AERPE_Aeropyrum_pernix_Archaea SR54_PYRAE_Pyrobaculum_aerophilum_Archaea SR54_THEVO_Thermoplasma_volcanium_Archaea SR54_THEAC_Thermoplasma_acidophilum_Archaea SR54_ARCFU_Archaeoglobus_fulgidus_Archaea SR54_HALN1_Halobacterium_sp_Archaea SR54_METMA_Methanosarcina_mazei_Archaea SR54_METAC_Methanosarcina_acetivorans_Archaea SR54_METKA_Methanopyrus_kandleri_Archaea Q9HJ93_Thermoplasma_acidophilum_Archaea Q97BC4_Thermoplasma_volcanium_Archaea Q9YD31_Aeropyrum_pernix_Archaea Q980G1_Sulfolobus_solfataricus_Archaea Q8TUY8_Methanopyrus_kandleri_Archaea Q8TIN7_Methanosarcina_acetivorans_Archaea Q8PYQ0_Methanosarcina_mazei_Archaea O28217_Archaeoglobus_fulgidus_Archaea Q9HMN3_Halobacterium_sp_Archaea Y291_METJA_Methanococcus_jannaschii_Archaea Q8U051_Pyrococcus_furiosus_Archaea Q9V1C5_Pyrococcus_abyssi_Archaea O59331_Pyrococcus_horikoshii_Archaea O27645_Methanobacterium_thermoautotrophicum_Archaea Q8ZTT8_Pyrobaculum_aerophilum_Archaea Q8YW57_Anabaena_sp_Bacteria Q8DKD1_Synechococcus_elongatus_Bacteria Q9WZ40_Thermotoga_maritima_Bacteria_1VMA Q8G736_Bifidobacterium_longum_Bacteria Q8NNW8_Corynebacterium_glutamicum_Bacteria Q8FP21_Corynebacterium_efficiens_Bacteria FTSY_MYCLE_Mycobacterium_leprae_Bacteria Q9ZBP9_Streptomyces_coelicolor_Bacteria BAC70365_Streptomyces_avermitilis_Bacteria Q9RS67_Deinococcus_radiodurans_Bacteria AAN44941_Shigella_flexneri_Bacteria Q8X6R2_Escherichia_coli_Bacteria Q8FCP0_Escherichia_coli_Bacteria Q8ZLE9_Salmonella_typhimurium_Bacteria Q8Z251_Salmonella_typhi_Bacteria Q8ZAI8_Yersinia_pestis_Bacteria Q8E8S5_Shewanella_oneidensis_Bacteria Q9CKT7_Pasteurella_multocida_Bacteria FTSY_HAEIN_Haemophilus_influenzae_Bacteria Q9KVJ6_Vibrio_cholerae_Bacteria Q8DD58_Vibrio_vulnificus_Bacteria Q87KM1_Vibrio_parahaemolyticus_Bacteria Q8D3D0_Wigglesworthia_brevipalpis_Bacteria FTSY_BUCAP_Buchnera_aphidicola_Bacteria Q9I6C1_Pseudomonas_aeruginosa_Bacteria Q88AG3_Pseudomonas_syringae_Bacteria Q88CR9_Pseudomonas_putida_Bacteria AAO91394_Coxiella_burnetii_Bacteria Q8P831_Xanthomonas_campestris_Bacteria Q9PC71_Xylella_fastidiosa_Bacteria Q87D08_Xylella_fastidiosa_Bacteria CAD85326_Nitrosomonas_europaea_Bacteria Q8Y2F0_Ralstonia_solanacearum_Bacteria FTSY_NEIMB_Neisseria_meningitidis_Bacteria FTSY_NEIMA_Neisseria_meningitidis_Bacteria Q8KFX0_Chlorobium_tepidum_Bacteria Q8A9A1_Bacteroides_thetaiotaomicron_Bacteria Q9A287_Caulobacter_crescentus_Bacteria Q89X49_Bradyrhizobium_japonicum_Bacteria Q8YJF2_Brucella_melitensis_Bacteria Q8FYE8_Brucella_suis_Bacteria Q92L48_Rhizobium_meliloti_Bacteria Q98EB4_Rhizobium_loti_Bacteria Q92GB8_Rickettsia_conorii_Bacteria FTSY_RICPR_Rickettsia_prowazekii_Bacteria Q8R9W8_Thermoanaerobacter_tengcongensis_Bacteria Q8XJP1_Clostridium_perfringens_Bacteria Q97IA0_Clostridium_acetobutylicum_Bacteria Q895M6_Clostridium_tetani_Bacteria Q98PP5_Mycoplasma_pulmonis_Bacteria Q8EVS5_Mycoplasma_penetrans_Bacteria FTSY_MYCPN_Mycoplasma_pneumoniae_Bacteria FTSY_MYCGE_Mycoplasma_genitalium_Bacteria Q9PR03_Ureaplasma_parvum_Bacteria Q92AK5_Listeria_innocua_Bacteria Q8Y693_Listeria_monocytogenes_Bacteria AAP27713_Bacillus_anthracis_Bacteria AAP10767_Bacillus_cereus_Bacteria FTSY_BACSU_Bacillus_subtilis_Bacteria Q8CXH4_Oceanobacillus_iheyensis_Bacteria Q9KA08_Bacillus_halodurans_Bacteria AAO82775_Enterococcus_faecalis_Bacteria Q88WJ8_Lactobacillus_plantarum_Bacteria Q9CHB9_Lactococcus_lactis_Bacteria Q8E677_Streptococcus_agalactiae_Bacteria Q8E0K4_Streptococcus_agalactiae_Bacteria Q8CWX8_Streptococcus_mutans_Bacteria Q8DPK2_Streptococcus_pneumoniae_Bacteria Q9A0X7_Streptococcus_pyogenes_Bacteria Q8K891_Streptococcus_pyogenes_Bacteria Q8CPH9_Staphylococcus_epidermidis_Bacteria Q99UN5_Staphylococcus_aureus_Bacteria Q8NX08_Staphylococcus_aureus_Bacteria O80842_Arabidopsis_thaliana_Eukaryota FTSY_AQUAE_Aquifex_aeolicus_Bacteria O83587_Treponema_pallidum_Bacteria O51103_Borrelia_burgdorferi_Bacteria Q9PN89_Campylobacter_jejuni_Bacteria FTSY_HELPJ_Helicobacter_pylori_Bacteria AAP05526_Chlamydophila_caviae_Bacteria Q9PLA0_Chlamydia_muridarum_Bacteria O84827_Chlamydia_trachomatis_Bacteria SR54_ECO57_Escherichia_coli_Bacteria_1DUL SR54_THEAQ_Thermus_aquaticus_Bacteria_1FFH SR54_HUMAN_Homo_sapiens_Eukaryota_1MFQ SR54_ACIAM_Acidianus_ambivalens_Archaea_1J8M SR54_SULSO_Sulfolobus_solfataricus_Archaea_1QZW FTSY_THEAQ_Thermus_aquaticus_Bacteria_1OKK FTSY_ECOLI_Escherichia_coli_Bacteria_1FTS rel. ASA contact order salt bridges/residue E. coli Thermus aquaticus T. maritima Sulfolobus solfataricus Acidianus ambivalens Thermus aquaticus more compact slightly more salt bridges less compact much more salt bridges archeal + eukaryotic paralogs bacterial paralogs bacterial orthologs Different proteins adapt to thermostability in different ways (even homologs) protein families with 1 T. maritima structure 1 mesophilic structure 1 other thermophilic structure -> 7/8 different features for thermostability in different species overall, no significant correlation in features between thermophilic species (p > 0.05) different proteins adapt to thermostability by different features proteins in different species adapt to thermostability by different features Different proteins adapt to thermostability in different ways (even homologs) Conclusions concerning T. maritima features of ionic interactions and compactness are relevant to 96% of protein pairs some previously reported features are not significant (notably H bonds, IV structure) paralogs follow the same trends as orthologs, with more divergence T. maritima proteins are representative of thermophiles different proteins follow different strategies: between families inside families (homologs) link to IV structure evolution An evolutionary framework has brought input to structural genomics Perspectives: what can structural genomics bring to evolutionary studies? Structural coverage of the T. maritima genome as a function of PDB growth (or time). Annotation method: blue, FFAS score 30%; red, sequence identity >95%. Friedberg et al Current Op Struct Biol 14: more and more protein families have at least one structure -> modeling of all family members -> evolution by speciation or duplication at the structure level more and more protein families or superfamilies have >2 structures -> study the evolution of protein structure Conclusion and aknowledgements structural genomics promises to add a level of information to genomics and transcriptomics will it hold its promise? will we know to make the best of it? Joint Center for Structural Genomics & Burnham Institute (San Diego) Andreu Alibs Adam Godzik Universit de Lausanne Grigoris Amoutzias Gilles Parmentier Romain Studer