Picking a face from the crowd

Protein–Protein Recognitionedited by Colin Kleanthous Oxford University Press, 2000. £35 (pbk), £69.50 (hbk) (334 pages) ISBN 0199637601Most biological processes are absolutely dependent on the formation of specific interactions between proteins that spend part of their lives as independent entities. Enormous effort has been expended in recent years to catalog these interactions and their functional consequences, with the delineation of the ‘circuitry’ describing complex biological events as one major goal. Alongside this research into the ‘what’ of protein–protein interactions, a parallel, if somewhat less visible, effort has been ongoing to understand the ‘how’; that is, the physicochemical basis for protein–protein recognition. Three-dimensional structures have now been determined for >100 complexes and, in many instances, these have been complemented by extensive mutational and thermodynamic studies.This area is not only of fundamental academic interest, but also has importance for the design of drugs to impact on protein–protein (and, indeed, other molecular) interactions. Protein–Protein Recognition is, to my knowledge, the first book devoted entirely to this subject. Its nine chapters, all by prominent experts in the field, comprise two overviews on general kinetic, thermodynamic and structural aspects of protein–protein interactions, followed by seven structurally oriented chapters focusing on specific systems (i.e. electron transfer proteins, integrins, major histocompatibility complex proteins, antibodies, signal transduction complexes, proteinase inhibitors and nuclease inhibitors), loosely organized into three sections according to complex stability.Excellent review articles on nearly all the topics covered by this book have been published recently. I therefore had to ask whether or not the book offers readers anything beyond what they might derive from these other sources. Does it make the subject more accessible? Is it more comprehensive? Is it cohesive? By the very juxtaposition of so many diverse systems, does it challenge readers to consider certain issues differently than they otherwise might? The answer is yes.The opening chapter on kinetics and thermodynamics sets the stage for subsequent case studies well, providing a solid introduction to the terminology, methodologies and conceptual framework, with appropriate cautions regarding popular approaches for measuring and characterizing protein–protein interactions. It also previews nicely some of the ideas recurring through multiple chapters, as well as individual systems themselves. The next chapter, on structural analysis and classification of protein–protein interactions, is less successful. The discussion is couched primarily in terms of similarities and differences between permanent complexes (those between subunits in multimeric proteins) and non-obligate complexes, an emphasis that is largely irrelevant to the central issue of ‘recognition’. Even for this type of comparative analysis, the readers might do better to consult the more detailed classic piece published by the same authors in 1996 [1xPrinciples of protein–protein interactions. Jones, S and Thornton, J.M. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 13–20Crossref | PubMed | Scopus (1840)See all References][1].The large assortment of systems presented in the main body of the book is remarkably diverse with respect to the stabilities of the complexes (Kd values range from millimolar down to sub-femtomolar), the recognition ‘strategies’ developed by nature, and the biological purposes served; the intimate relationship between these aspects is emphasized in several of the chapters. The levels of knowledge and understanding that have been achieved for these systems are also varied. In some chapters, we read in great detail about the atomic interactions revealed by high-resolution structures as well as about what mutational and calorimetric data (and sometimes structures of variant complexes) have revealed about their nature and importance. In others, definitive structural information on complexes has been less forthcoming and it has been necessary to speculate on the basis of selected pieces of the puzzle. However, throughout the book, the authors consistently and carefully distinguish fact from hypothesis, and stress both the limitations of the pictures presented and the questions still to be addressed.Biochemists at all levels who wish to get an overview of this exciting and burgeoning field, or to familiarize themselves with the individual systems described, will find this book of considerable interest. Overall, it is readable and logical, with abundant background, history and illustrations, although the chapters on integrins and signal transduction might be slightly rough going for those with little prior knowledge of these fields and their elaborate terminologies. Although about two years have passed since most of the chapters were written, I am aware of only one area (integrins) in which the intervening time has seen a truly major breakthrough that might dictate significant revision of the text. Unavoidably, some prominent systems are missing, but the only irksome absence (for me) is the complex between human growth hormone and its receptor, an extremely well-characterized interaction that was the subject of pioneering studies in the field.In addition to the general audience, researchers such as myself who are active in one area of protein–protein recognition, but wish to expand their horizons, should find the book to be of great value. As someone working with very tight complexes, the questions I usually think about concern details of the binding interface and how these translate into avidity and specificity. This collection provides easy access to a wealth of potentially useful information along these lines on other systems but, at the same time, has taught me that such questions can sometimes be beside the point. How does one dissect the precise ‘contributions’ of specific intermolecular contacts or discern whether a complex contains energetic ‘hot spots’ when association entails drastic restructuring (as in many of the signal transduction complexes), or when the complexes do not even have a single defined structure (as suggested for some of the weakly associating electron transport proteins)? Likewise, researchers studying the low-affinity and/or conformationally plastic systems might find themselves surprised at how far knowledge about the energetic side has progressed for a select few complexes.