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Doctoral Thesis
DOI
10.11606/T.76.2009.tde-26032009-130135
Document
Author
Full name
Lucas Bleicher
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Carlos, 2009
Supervisor
Committee
Polikarpov, Igor (President)
Bisch, Paulo Mascarello
Costa Filho, Antônio José da
Farah, Shaker Chuck
Skaf, Munir Salomão
Title in Portuguese
Implementação da análise de acoplamentos estatísticos e sua aplicação à família de proteínas tirosina fosfatases
Keywords in Portuguese
Análise de Acoplamentos Estatísticos
Arsenato Redutases
Cristalografia de Proteínas
Interleucina-22
Laminarinase
Proteínas tirosina fosfatases
Abstract in Portuguese
A Análise de Acoplamentos Estatísticos é uma técnica computacional capaz de identificar resíduos importantes para a estrutura e função de proteínas em uma família por meio da quantificação de conservação posicional, correlação entre posições e identificação de grupos de resíduos correlacionados entre si. Neste trabalho, a análise de acoplamentos estatísticos foi implementada e aplicada ao estudo das proteínas tirosina fosfatases. Em conjunto com as proteínas tirosina quinases (PTKs), que adicionam um grupo fosforil a um resíduo de tirosina em uma proteína, as proteínas tirosina fosfatases (PTPs), que o removem, são responsáveis por diversos processos de sinalização celular. Elas são um caso de evolução convergente, onde um subgrupo (as proteínas tirosina fosfatases de baixo peso molecular) não apresenta homologia às chamadas PTPs "clássicas", capazes de defosforilar apenas resíduos de tirosina, e às fosfatases de especifidicade dupla, capazes de defosforilar também resíduos de serina e treonina, além de substratos não-protéicos. Em comum, as três subfamílias apresentam apenas o motivo CX5R, característico para todas as PTPs. Através do estudo das três subfamílias utilizando a análise de acoplamentos estatísticos, foi possível obter uma descrição detalhada de suas características conservadas e correlacionadas, relacionando-as ao conhecimento acumulado sobre proteínas tirosina fosfatases e a questões em aberto como a regulação por dimerização, a especificidade e mutações relacionadas a patologias. Foi possível também apresentar um método capaz de distinguir proteínas tirosina fosfatases de baixo peso molecular das arsenato redutases, derivadas das primeiras por evolução divergente. Adicionalmente, a técnica foi aplicada ao estudo das hexoquinases, às superóxido dismutases e às peroxidases. A tese descreve também estudos desenvolvidos pelo autor na área de cristalografia de proteínas a determinação das estruturas da Transtirretina humana em complexo com genisteína, da holo-Hexoquinase PI de S. cerevisae, do complexo IL-22/IL-22R1 e da Laminarinase de R. marinus.
Title in English
Implementation of the statistical coupling analysis and its application to the Protein Tyrosine Phosphatases family.
Keywords in English
Arsenate reductases. Protein crystallography
Interleukin-22
Laminarinase
Protein tyrosine phosphatases
Statistical coupling analysis
Abstract in English
The statistical coupling analysis is a computational technique which can identify important residues for the structure and function of proteins in a family by quantifying positional conservation, correlation between positions and identifying groups of self-correlating residues. Its implementation in this research group was applied to the study of the protein tyrosine phosphatases. Together with the protein tyrosine kinases (PTKs), which add a phosphoryl group to a tyrosine residue in proteins, the protein tyrosine phosphatases (PTPs), which remove it, are responsible for a variety of cell signaling processes. They are a case of convergent evolution, since one subgroup (the low molecular weight protein tyrosine phosphatases) are not homologous to the classical phosphatases, which can only dephosphorilate tyrosine residues, and the dual-specificity phosphatases, which can also dephosphorilate serine and threonine residues, and also non-proteinaceous substrates. All three sub-families have, in common, the CX5R motif, a characteristic of all PTPs. By applying the statistical coupling analysis to the study of the three sub-families, it was possible to obtain a detailed depiction of their conserved and correlated characteristics, relating them to the accumulated knowledge on protein tyrosine phosphatases and open questions such as protein regulation by dimerization, specificity and disease-related mutations. It was also possible to present a method to distinguish between low molecular weight phosphatases and arsenate reductases, which are derived by the former by divergent evolution. In addition, the technique was applied to the study of hexokinases, superoxide dismutases and peroxidases. The thesis also describe studies developed by the author in the field of protein crystallography the structure determination of human transthyretin in complex with genistein, holo-hexokinase PI from S. cerevisae, the IL-22/IL-22R1 complex and the laminarinase from R. marinus.
 
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Publishing Date
2009-04-08
 
WARNING: The material described below relates to works resulting from this thesis or dissertation. The contents of these works are the author's responsibility.
  • BACHEGA, Jose Fernando Ruggiero, et al. Systematic structural studies of iron superoxide dismutases from human parasites and a statistical coupling analysis of metal binding specificity [doi:10.1002/prot.22412]. Proteins: Structure, Function, and Bioinformatics [online], 2009, vol. 77, n. 1, p. 26-37.
  • BLEICHER, Lucas, et al. Crystal structure of the IL-22/IL-22R1 complex and its implications for the IL-22 signaling mechanism [doi:10.1016/j.febslet.2008.07.046]. FEBS Letters [online], 2008, vol. 582, n. 20, p. 2985-2992.
  • BLEICHER, Lucas, et al. Molecular Basis of the Thermostability and Thermophilicity of Laminarinases : X-ray Structure of the Hyperthermostable Laminarinase from [doi:10.1021/jp200330z]. The Journal of Physical Chemistry B [online], 2011, vol. 115, n. 24, p. 7940-7949.
  • DE MOURA, Patricia Ribeiro, et al. Crystal structure of a soluble decoy receptor IL-22BP bound to interleukin-22 [doi:10.1016/j.febslet.2009.03.006]. FEBS Letters [online], 2009, vol. 583, n. 7, p. 1072-1077.
  • GOLUBEV, Alexander, et al. Crystallization and Preliminary Crystallographic Analysis of Laminarinase from Rhodothermus marinus : A Case of Pseudomerohedral Twinning [doi:10.2174/092986608786071139]. Protein & Peptide Letters [online], 2008, vol. 15, n. 10, p. 1142-1144.
  • KUSER, Paula, et al. Crystal structure of yeast hexokinase PI in complex with glucose : A classical “induced fit” example revised [doi:10.1002/prot.21956]. Proteins: Structure, Function, and Bioinformatics [online], 2008, vol. 72, n. 2, p. 731-740.
  • TRIVELLA, Daniela B.B., et al. Conformational differences between the wild type and V30M mutant transthyretin modulate its binding to genistein : Implications to tetramer stability and ligand-binding [doi:10.1016/j.jsb.2010.03.002]. Journal of Structural Biology [online], 2010, vol. 170, n. 3, p. 522-531.
  • WATANABE, Leandra, et al. Crystal structure and statistical coupling analysis of highly glycosylated peroxidase from royal palm tree (Roystonea regia) [doi:10.1016/j.jsb.2009.10.009]. Journal of Structural Biology [online], 2010, vol. 169, n. 2, p. 226-242.
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