1 Protein – Protein Interactions : An Overview

Protein–protein interactions (PPIs) are implicated in almost all biological processes for any given protein engaged in complexes with other proteins for themajority of its lifetime. In this regard, proteins function not merely as single, isolated entities, but display their roles by interacting with other cellular components. The different interaction patterns are at least as important as the intrinsic biochemical activity status (e.g., of a protein kinase) of the protein itself. Therefore, to understand the biological role of a protein it is of the utmost importance to know the underlying PPI network. This holds especially true in the case of diseases where, for example, mutations in oncogene or tumor suppressor proteins are recognized as the cause for malignancies. An impressive recent example for the relevance of the PPI interplay is the finding that active-site inhibitors targeting the oncogenic kinase B-Raf can under certain circumstances activate the underlying signal transduction pathway (mitogen-activated protein kinase (MAPK) pathway) instead of inhibiting it [1–3]. This finding is a strong reminder that nature in the majority of cases ultimately relies on regulating protein function by PPIs. In addition to taking into account this important concept for the drug development process, targeting PPIs significantly enlarges the “druggable genome” that was initially estimated to comprise around 1500 single protein targets [4]. While this number is still several times higher than the 266 human protein targets actually addressed by currently approved drugs [5], there are diseases that lack a good “conventional” target like an enzyme, receptor, or ion channel. By adding the number of PPIs occurring in the human body, the so-called protein–protein “interactome,” this situation will definitely be improved. As the size of the interactome has been estimated to lie between 130 000 [6] and 650 000 [7], successfully addressing PPIs will vastly expand our opportunities for pharmacological intervention.