Structural analysis of protein interaction networks

Abstract

Interactions between proteins give rise to many functions in cells. In the lastdecade, highthroughput experiments have identified thousands of protein interactions, which are often represented together as large protein interaction networks. However, the classical way of representing interaction networks, as nodes and edges, is too limited to take dynamic properties such as compatible and mutually exclusive interactions into account. In this work, we study protein interaction networks using structural information. More specifically, the analysis of protein interfaces in threedimensional protein structures enables us to identify which interfaces are compatible and which are not. Based on this principle, we have implemented a method, which aims at the analysis of protein interaction networks from a structural point of view by (1) predicting possible binary interactions for proteins that have been found in complex experimentally and (2) identifying possible mutually exclusive and compatible complexes. We validated our method by using positive and negative reference sets from literature and set up an assay to benchmark the identification of compatible and mutually exclusive structural interactions. In addition, we reconstructed the protein interaction network associated with the G proteincoupled receptor Rhodopsin and defined related functional submodules by combining interaction data with structural analysis of the network. Besides its established role in vision, our results suggest that Rhodopsin triggers two additional signaling pathways towards (1) cytoskeleton dynamics and (2) vesicular trafficking.

Las funciones de las proteínas resultan de la manera con la que interaccionan entre ellas. Los experimentos de alto rendimiento han permitido identificar miles de interacciones de proteínas que forman parte de redes grandes y complejas. En esta tesis, utilizamos la información de estructuras de proteínas para estudiar las redes de interacciones de proteínas. Con esta información, se puede entender como las proteínas interaccionan al nivel molecular y con este conocimiento se puede identificar las interacciones que pueden ocurrir al mismo tiempo de las que están incompatibles. En base a este principio, hemos desarrollado un método que permite estudiar las redes de interacciones de proteínas con un punto de vista mas dinámico de lo que ofrecen clásicamente. Además, al combinar este método con minería de la literatura y Los datos de la proteomica hemos construido la red de interacciones de proteínas asociada con la Rodopsina, un receptor acoplado a proteínas G y hemos identificado sus sub--‐módulos funcionales. Estos análisis surgieron una novel vıa de señalización hacia la regulación del citoesqueleto y el trafico vesicular por Rodopsina, además de su papel establecido en la visión.

Programa de doctorat en Biomedicina