title: The Evolving Contribution of Mass Spectrometry to Integrative Structural Biology.
abstract: Protein complexes are key catalysts and regulators for the majority of cellular processes. Unveiling their assembly and structure is essential to understanding their function and mechanism of action. Although conventional structural techniques such as X-ray crystallography and NMR have solved the structure of important protein complexes, they cannot consistently deal with dynamic and heterogeneous assemblies, limiting their applications to small scale experiments. A novel methodological paradigm, integrative structural biology, aims at overcoming such limitations by combining complementary data sources into a comprehensive structural model. Recent applications have shown that a range of mass spectrometry (MS) techniques are able to generate interaction and spatial restraints (cross-linking MS) information on native complexes or to study the stoichiometry and connectivity of entire assemblies (native MS) rapidly, reliably, and from small amounts of substrate. Although these techniques by themselves do not solve structures, they do provide invaluable structural information and are thus ideally suited to contribute to integrative modeling efforts. The group of Brian Chait has made seminal contributions in the use of mass spectrometric techniques to study protein complexes. In this perspective, we honor the contributions of the Chait group and discuss concepts and milestones of integrative structural biology. We also review recent examples of integration of structural MS techniques with an emphasis on cross-linking MS. We then speculate on future MS applications that would unravel the dynamic nature of protein complexes upon diverse cellular states. Graphical Abstract ᅟ.
authors.affiliation: Department of Biology, Institute of Molecular Systems Biology, ETH Zürich, 8093, Zürich, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Faini
authors.affiliation: Department of Biology, University of Konstanz, 78457, Konstanz, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Stengel
authors.affiliation: Department of Biology, Institute of Molecular Systems Biology, ETH Zürich, 8093, Zürich, Switzerland. aebersold@imsb.biol.ethz.ch.|Faculty of Science, University of Zürich, Zürich, Switzerland. aebersold@imsb.biol.ethz.ch.
authors.forename: Ruedi
authors.initials: R
authors.lastname: Aebersold
mesh_terms: D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D011506:Proteins / Q000737:chemistry*
chemical_list: D011506:Proteins
keywords: Affinity purification MS; CX-MS; Cross-linking mass spectrometry; Hybrid modeling; Integrative structural biology; Native MS; Protein complexes; Structural mass spectrometry; XL-MS