At the Interface of Interaction Proteomics and Structural Biology

Abstract

In this special issue, several articles describing some of the recent progress made at the interface of two exciting research areas of interest to the readership of Molecular and Cellular Proteomics, namely interaction proteomics and structural biology, are presented. The use of affinity purification in combination with mass spectrometry to map protein-protein interaction networks has provided much new insight into the molecular organization of the cell. The general view has emerged that most biological processes involve regulated cooperation between multiple protein subunits in both time and space. Large scale studies as well as highly targeted affinity purification studies in combination with mass spectrometry have provided an important framework (or catalogue) of all possible protein interaction networks. However, further in-depth structural and functional characterization of these complexes is essential not only to validate these data sets but also to understand their dynamics and specific functional role in biological processes. High resolution structural features of proteins and protein complexes can be determined by methods such as nuclear magnetic resonance, x-ray crystallography, and various forms of microscopy (e.g. electron microscopy and atomic force microscopy). Structural high resolution data on protein complexes provide extremely valuable insights into their mechanisms at the molecular level; however, with some notable exceptions, obtaining structures of large, heterogeneous, and/or transient protein complexes, particularly in multiple regulatory states, remains challenging and labor-intensive. New technologies and/or linking of existing technologies is indispensable to bridge the gap between large scale, high throughput interaction proteomics and high resolution, lower throughput structural biology. Whereas interaction proteomics often still lacks detailed information about structure, dynamics, and function, classical structural biology approaches are still often limited by the size of the system studied and the sensitivity of the methods and therefore are overly dependent on (over)expression of recombinant proteins, which do not optimally correlate with the in vivo appearing entities. In this issue, data from several emerging technologies are presented that may better connect interaction proteomics with structural biology. These include combinations of electron and/or atomic force microscopy and mass spectrometry. Moreover, results obtained via mass spectrometry-based methods complementary to more conventional structural biology methods, such as chemical cross-linking, hydrogen/ deuterium exchange, and native mass spectrometry, are presented. These approaches are used to analyze somewhat lower resolution structural details, albeit of exceedingly large and heterogeneous protein complexes, providing insights into their architecture and the conformational flexibility observed therein. Another important contribution in linking interaction proteomics and structural biology comes from various forms of computational structural biology, including assessing protein-protein interactions by information-driven docking, structural modeling, threading, and integrating diverse data for the structure determination of macromolecular assemblies. Through collaborative efforts between scientists of diverse backgrounds using computational, conventional structural biological, and mass spectrometry-based approaches, unique details on the constituency, stoichiometry, (dis)assembly, conformation, and temporal dynamics of important and large protein assemblies, such as the proteasome, the ribosome, the spliceosome, the nuclear pore complex, and even whole viruses and bacteriophages, are highlighted in this issue. This field is rapidly developing not only because of technological advances and increasing computing power but even more importantly because of the willingness of more and more people to work collaboratively at this interface of interaction proteomics and structural biology. The gap between the existing large inventories of protein complexes charted and the relatively small number of high resolution structures available will likely be steadily closed. This is important as it is essential information in understanding living systems at the molecular level. From the Biomolecular Mass Spectrometry and Proteomics Group, Bijvoet Center for Biomolecular Research, and Utrecht Institute for Pharmaceutical Sciences, Utrecht University and the Netherlands Proteomics Centre, Padualaan 8, 3584 CH Utrecht, The Netherlands ‡ To whom correspondence should be addressed. Tel.: 31-30-2536793; Fax: 31-30-253-6919; E-mail: a.j.r.heck@uu.nl. Published, MCP Papers in Press, June 3, 2010, DOI 10.1074/ mcp.E110.001511 Editorial