Human Cancer Protein-Protein Interaction Network: A Structural Perspective
Open Access
- 11 December 2009
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Computational Biology
- Vol. 5 (12), e1000601
- https://doi.org/10.1371/journal.pcbi.1000601
Abstract
Protein-protein interaction networks provide a global picture of cellular function and biological processes. Some proteins act as hub proteins, highly connected to others, whereas some others have few interactions. The dysfunction of some interactions causes many diseases, including cancer. Proteins interact through their interfaces. Therefore, studying the interface properties of cancer-related proteins will help explain their role in the interaction networks. Similar or overlapping binding sites should be used repeatedly in single interface hub proteins, making them promiscuous. Alternatively, multi-interface hub proteins make use of several distinct binding sites to bind to different partners. We propose a methodology to integrate protein interfaces into cancer interaction networks (ciSPIN, cancer structural protein interface network). The interactions in the human protein interaction network are replaced by interfaces, coming from either known or predicted complexes. We provide a detailed analysis of cancer related human protein-protein interfaces and the topological properties of the cancer network. The results reveal that cancer-related proteins have smaller, more planar, more charged and less hydrophobic binding sites than non-cancer proteins, which may indicate low affinity and high specificity of the cancer-related interactions. We also classified the genes in ciSPIN according to phenotypes. Within phenotypes, for breast cancer, colorectal cancer and leukemia, interface properties were found to be discriminating from non-cancer interfaces with an accuracy of 71%, 67%, 61%, respectively. In addition, cancer-related proteins tend to interact with their partners through distinct interfaces, corresponding mostly to multi-interface hubs, which comprise 56% of cancer-related proteins, and constituting the nodes with higher essentiality in the network (76%). We illustrate the interface related affinity properties of two cancer-related hub proteins: Erbb3, a multi interface, and Raf1, a single interface hub. The results reveal that affinity of interactions of the multi-interface hub tends to be higher than that of the single-interface hub. These findings might be important in obtaining new targets in cancer as well as finding the details of specific binding regions of putative cancer drug candidates. Protein-protein interaction networks provide a global picture of cellular function and biological processes. The dysfunction of some interactions causes many diseases, including cancer. Proteins interact through their interfaces. Therefore, studying the interface properties of cancer-related proteins will help explain their role in the interaction networks. The structural details of interfaces are immensely useful in efforts to answer some fundamental questions such as: (i) what features of cancer-related protein interfaces make them act as hubs; (ii) how hub protein interfaces can interact with tens of other proteins with varying affinities; and (iii) which interactions can occur simultaneously and which are mutually exclusive. Addressing these questions, we propose a method to characterize interactions in a human protein-protein interaction network using three-dimensional protein structures and interfaces. Protein interface analysis shows that the strength and specificity of the interactions of hub proteins and cancer proteins are different than the interactions of non-hub and non-cancer proteins, respectively. In addition, distinguishing overlapping from non-overlapping interfaces, we illustrate how a fourth dimension, that of the sequence of processes, is integrated into the network with case studies. We believe that such an approach should be useful in structural systems biology.Keywords
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