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Open Access Research

Modular architecture of protein structures and allosteric communications: potential implications for signaling proteins and regulatory linkages

Antonio del Sol1*, Marcos J Araúzo-Bravo1, Dolors Amoros1 and Ruth Nussinov23

Author Affiliations

1 Bioinformatics Research Unit, Research and Development Division, Fujirebio Inc., Komiya-cho, Hachioji-shi, Tokyo 192-0031, Japan

2 Basic Research Program, SAIC-Frederick, Inc., Center for Cancer Research, Nanobiology Program, National Cancer Institute, Frederick, MD 21702, USA

3 Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Tel Aviv University, Tel Aviv 69978, Israel

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Genome Biology 2007, 8:R92  doi:10.1186/gb-2007-8-5-r92

Published: 25 May 2007

Abstract

Background

Allosteric communications are vital for cellular signaling. Here we explore a relationship between protein architectural organization and shortcuts in signaling pathways.

Results

We show that protein domains consist of modules interconnected by residues that mediate signaling through the shortest pathways. These mediating residues tend to be located at the inter-modular boundaries, which are more rigid and display a larger number of long-range interactions than intra-modular regions. The inter-modular boundaries contain most of the residues centrally conserved in the protein fold, which may be crucial for information transfer between amino acids. Our approach to modular decomposition relies on a representation of protein structures as residue-interacting networks, and removal of the most central residue contacts, which are assumed to be crucial for allosteric communications. The modular decomposition of 100 multi-domain protein structures indicates that modules constitute the building blocks of domains. The analysis of 13 allosteric proteins revealed that modules characterize experimentally identified functional regions. Based on the study of an additional functionally annotated dataset of 115 proteins, we propose that high-modularity modules include functional sites and are the basic functional units. We provide examples (the Gαs subunit and P450 cytochromes) to illustrate that the modular architecture of active sites is linked to their functional specialization.

Conclusion

Our method decomposes protein structures into modules, allowing the study of signal transmission between functional sites. A modular configuration might be advantageous: it allows signaling proteins to expand their regulatory linkages and may elicit a broader range of control mechanisms either via modular combinations or through modulation of inter-modular linkages.