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Structural characterization of alpha-4 and TipRL proteins and their complexes with the catalytic subunits of type 2A phosphatases

Grant number: 06/06234-0
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): March 01, 2007
Effective date (End): June 30, 2008
Field of knowledge:Biological Sciences - Biophysics
Principal Investigator:Nilson Ivo Tonin Zanchin
Grantee:Gustavo Arruda Bezerra
Home Institution: Laboratório Nacional de Luz Síncrotron (LNLS). Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia, Inovações e Comunicações (Brasil). Campinas , SP, Brazil

Abstract

The rapamycin-sensitive signaling (or TOR signaling pathway – Target Of Rapamycin) is responsible for the control of processes related to the cellular growth in eukaryotic organisms. Changes in its functioning are directly related to diseases like cancer and diabetes. TOR, the central protein kinase of this pathway, acts through the phosphorylation of diverse substrates, resulting in transcription and translation modulation of several genes and in cell morphology control. In mammals, the association between Alpha-4 protein and the catalytic subunit of the phosphatase PP2A (PP2Ac) results in the inhibition of the transcription inhibitor 4E-BP1, a process that regulates the translation factor eIF4E activity which is mediated by the TOR signaling pathway. The evidence that Alpha-4 also binds to PP4 and PP6, changing their activities, suggests a fundamental role of these interactions in the TOR pathway signaling. However, little is known of how these interactions occur, since there is no structural explanation for the mechanism of action and regulatory function of these proteins. In this context, the present project aims to elucidate the three-dimensional structures of Alpha-4 and TipRL (Alpha-4 regulator) and their complexes with phophatases (PP2Ac, PP4c and PP6c), by X-ray crystallogaphy. Since the activity of these proteins involves the reversible formation of complexes according to physiological signals and environment stimulations, solving the three-dimensional structures of these molecules and their complexes allows to understand the molecular mechanism for which the TOR pathway is regulated and its implication in the metabolism.