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Universidade Federal De Goiás Programa De Pós-Graduação Em Medicina Tropical E Saúde Pública

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Universidade Federal De Goiás Programa De Pós-Graduação Em Medicina Tropical E Saúde Pública UNIVERSIDADE FEDERAL DE GOIÁS PROGRAMA DE PÓS-GRADUAÇÃO EM MEDICINA TROPICAL E SAÚDE PÚBLICA MARIELLE GARCIA SILVA ANÁLISE PROTEÔMICA DE MEMBRANAS DE Paracoccidioides sp. DURANTE PRIVAÇÃO DE ZINCO Orientadora: Dra. Célia Maria de Almeida Soares Goiânia 2014 2 UNIVERSIDADE FEDERAL DE GOIÁS PROGRAMA DE PÓS-GRADUAÇÃO EM MEDICINA TROPICAL E SAÚDE PÚBLICA MARIELLE GARCIA SILVA ANÁLISE PROTEÔMICA DE MEMBRANAS DE Paracoccidioides sp. DURANTE PRIVAÇÃO DE ZINCO Dissertação apresentada ao Programa de Pós-Graduação em Medicina Tropical e Saúde Pública da Universidade Federal de Goiás como requisito para obtenção do Título de Mestre em Medicina Tropical e Saúde Pública. Orientador: Prof. Dra. Célia Maria de Almeida Soares Goiânia 2014 ii iii Programa de Pós-Graduação em Medicina Tropical e Saúde Pública da Universidade Federal de Goiás BANCA EXAMINADORA DA DISSERTAÇÃO DE MESTRADO Aluno (a): Marielle Garcia Silva Orientador (a): Profª. Dra. Célia Maria de Almeida Soares MEMBROS Dr. Célia Maria de Almeida Soares Instituto de Ciências Biológicas, Universidade Federal de Goiás Dra. Luciana Casaletti Instituto de Ciências Biológicas, Universidade Federal de Goiás Dra. Patrícia de Sousa Lima Instituto de Ciências Biológicas, Universidade Federal de Goiás DATA: 04/08/2014 iv Dedico este trabalho ás pessoas mais importantes da minha vida... ... meus pais José e Lucélia, que sempre fizeram de tudo para me oferecer boa educação e sempre me apoiaram nas decisões tomadas. ... à minha irmã Mirelle, que sempre me ajudou nas tarefas e decisões. Obrigada pelo apoio! Se não fossem vocês, hoje não estaria onde estou! Obrigada por tudo! Amo vocês! v AGRADECIMENTOS A Deus, pela oportunidade da vida e por me abençoar a cada dia. À minha orientadora Célia Maria de Almeida Soares, por me receber no seu grupo de trabalho. Agradeço pela orientação e pela confiança em mim depositada. Pelo esforço em oferecer aos seus alunos condições para realização de trabalho de qualidade. Admiro sua competência e profissionalismo na coordenação do laboratório. Ao meu cunhado Alexandre, que nunca negou ajuda durante a realização dos experimentos. Obrigada pelo apoio, pelas sugestões e pela amizade. Aos professores do Laboratório de Biologia Molecular, da Universidade Federal de Goiás, Maristela Pereira, Alexandre Bailão, Clayton Borges Juliana Parente e Sílvia Salém-Izzac, pelo auxílio oferecido. Aos membros da banca de qualificação, Patrícia Lima, Lilian Baeza e Clayton Borges pelas sugestões e contribuições. À Juliana Santana, pelo companheirismo durante a realização dos experimentos e das discussões. Obrigada pela amizade profissional e pessoal. À Luciana, pela amizade, pelos conselhos e momentos de diversão. Obrigada pela ajuda durante a realização dos experimentos e por toda contribuição durante esses anos. Muito obrigada Lu. À Patrícia Lima, Elisa Flávia, Lucas Nojosa e Mariana Tomazett, pelos momentos de descontração, que ajudam a aliviar o cansaço durante o trabalho, e pela disponibilidade em sempre me ajudar. Obrigada a todos vocês! À Edilânia, Amanda, Danielle, Alessandro, Karla, Gabriel, Leandro Prado, André, Vanessa, Luiz Paulo, Igor, Fabiana, Leandro, Paula Francienete, Laura, Diandra, Laurine, Wesley, Lívia, Joyce, Kleber. Agradeço pelo convívio e contribuições. À todos os membros da minha família pelo apoio e palavras de incentivo. Obrigada pelas orações! vi SUMÁRIO Pág. LISTA DE ABREVIATURAS ix RESUMO x ABSTRACT xi 1. INTRODUÇÃO .............................................................................................. 12 1.1. Paracoccidioides spp. e Paracoccidioidomicose – Aspectos gerais .......... 12 1.2. Membranas celulares ................................................................................. 17 1.3. Importância dos íons metálicos em processos celulares ............................ 24 2. JUSTIFICATIVA ........................................................................................... 31 3. OBJETIVOS ................................................................................................... 32 3.1 Geral ........................................................................................................... 32 3.2 Específicos ................................................................................................. 32 4. MANUSCRITO .............................................................................................. 33 5. DISCUSSÃO ................................................................................................... 97 6. CONCLUSÃO................................................................................................. 100 7. PERSPECTIVAS ........................................................................................... 101 8. REFERÊNCIAS ............................................................................................. 102 vii LISTA DE FIGURAS E TABELAS Dissertação Pág. Figura 1: Morfologia de Paracoccidioides spp. 13 Figura 2: Distribuição geográfica da paracoccidioidomicose. 15 Figura 3: Aspectos clínicos da PCM. 16 Figura 4: Estrutura da membrana celular. 17 Figura 5: Associação das proteínas à membrana celular. 19 Figura 6: Proteínas de membrana ligadas a lipídeos. 21 Figura 7: Estrutura geral de uma âncora GPI ligando uma proteína à membrana 23 plasmática. Figura 8: Modelo do transporte de zinco. 27 Figura 9: Alinhamento de sequências de aminoácidos de S. cerevisiae, 28 Paracoccidioides spp. e espécies de Cryptococcus. Manuscrito Figura 1: Microscopia Eletrônica de Transmissão (MET) do extrato de membrana de 45 Paracoccidioides sp. Figura 2: Porcentagem de proteínas de membrana identificadas. 46 Figura 3: Proteínas de membrana reguladas. 46 Figure 4: Classificação funcional das proteínas de membrana. 47 Tabela 1: Proteínas de membrana identificadas em Paracoccidioides sp. na presença 48 ou na ausência de zinco. Tabela 2: Proteínas de membrana de Paracoccidioides sp. reprimidas em privação de 56 zinco e suas funções biológicas. Tabela 3: Proteínas de membrana de Paracoccidioides sp. induzidas em privação de 63 zinco e suas funções biológicas. Figura suplementar – 1 Tipo de detecção dos peptídeos para amostras do controle e de 65 privação de zinco. Figura suplementar – 2 Faixa de detecção dinâmica dos experimentos. 66 Figura suplementar – 3 Localização subcelular das proteínas identificadas 67 Tabela suplementar – 1 Proteínas reguladas em células de levedura de Paracoccidioides 68 sp. sob privação de zinco e as suas funções biológicas previstas. viii LISTA DE ABREVIATURAS PCM: Paracoccidioidomicose MET: Microscopia eletrônica de transmissão S1: Espécie 1 PS2: Espécie filogenética 2 PS3: Espécie filogenética 3 PS4: Espécie filogenética 4 DTT: Ditiotreitol TPEN: N,N,N_,N_- tetrakis (2-pyridyl-methyl) ethylenediamine - Quelante específico de zinco PIM: Proteínas integrais de membrana GPI: Glicosilfosfatidilinositol MPTs: Modificações pós-traducionais PATs: Palmitoil-transferases FTase: Farnesiltransferase Zrt1: Transportador de zinco de alta afinidade Zrt2: Transportador de zinco de baixa afinidade Irt1: Transportador de ferro CDF: Facilitador de difusão de cátions GM-CSF: Fator estimulante de colônias de granulócitos e macrófagos PA: Ácido fosfatídico LPA: Ácido lisofosfatídico 1-AGPAT: 1-acil-sn-glicerol-3-phosphate aciltransferase beta PS: Fosfatidilserina PI: Fosfatidilinositol PE: Fosfatidiletanolamina PC: Fosfatidilcolina Sac1: Fosfatase fosfoinositidica Dpm1: Dolicol fosfato manose sintase Mkc1: Proteína quinase ativada por mitógeno MMcM: Meio mínimo Mc Veigh Morton AF: Ammonium formate PLGS: ProteinLynx Global Server UPLC-MSE: Cromatografia de ultraperformace acoplada à espectrometria de massas ix RESUMO Paracoccidioides spp. são fungos patogênicos, causadores da paracoccidioidomicose, uma importante micose sistêmica nos países latino-americanos. O sucesso da infecção depende da capacidade do patógeno obter micronutrientes essenciais (metais) a partir do hospedeiro. Este processo de captação de nutrientes ocorre através de transportadores associados às membranas. As membranas são constituídas por uma bicamada lipídica com proteínas associadas e estão envolvidas em diferentes processos durante o estabelecimento da infecção, como transporte de nutrientes e regulação homeostática da célula. Como o zinco é um metal que desempenha um papel importante na regulação da interação patógeno-hospedeiro e distúrbios na homeostase deste micronutriente estão implicados na patogênese de doenças infecciosas, o objetivo deste estudo foi identificar as proteínas de membranas expressas em condições de privação de zinco. A técnica NanoUPLC-MSE foi empregada para identificar proteínas de membranas de células de levedura (Pb01) cultivadas em meio quimicamente definido na presença e ausência de zinco. Microscopia eletrônica de transmissão foi realizada para confirmar o enriquecimento da amostra com membranas. Posteriormente, as amostras foram digeridas e analisadas por NanoUPLC-MSE. Análises in silico foram realizadas para determinação da localização de 460 proteínas obtidas do extrato proteico de Pb01 cultivado em meio com zinco (controle) e TPEN (tratado). Do total de proteínas identificadas, 141 proteínas foram classificadas como pertencentes a membranas e destas, 120 proteínas foram reprimidas e 21 foram induzidas durante privação de zinco. Dentre as 141 proteínas de membranas, 81 apresentaram domínio transmembrana e 9 foram classificadas como sendo de membrana, em decorrência de modificação pós- traducional. Um total de 15 proteínas de membrana apresentou peptídeo sinal.
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