Current Opinion in Structural Biology

Accounting for conformational changes during protein-protein docking.

Publication Date: 2010 Feb 27 PMID: 20194014
Authors: Zacharias, M.
Journal: Curr Opin Struct Biol

Three-dimensional structures of only a small fraction of known protein-protein complexes are currently known. Meanwhile, computational methods are of increasing importance to provide structural models for known protein-protein interactions. Current protein-protein docking methods are often successful if experimentally determined partner proteins undergo little conformational changes upon binding. However, the realistic and computationally efficient treatment of conformational changes especially of the protein backbone during docking remains a challenge. New promising approaches of flexible refinement, ensemble docking and explicit inclusion of flexibility during the entire docking process have been developed. A significant fraction of known protein-protein interactions can be modeled based on homology to known protein-protein complexes which in many cases also requires efficient flexible refinement to provide accurate structural models.

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Molecular transformers in the cell: lessons learned from the DegP protease-chaperone.

Publication Date: 2010 Feb 24 PMID: 20188538
Authors: Sawa, J. - Heuck, A. - Ehrmann, M. - Clausen, T.
Journal: Curr Opin Struct Biol

Structure-function analysis of DegP revealed a novel mechanism for protease and chaperone regulation. Binding of unfolded proteins induces the oligomer reassembly from the resting hexamer (DegP6) into the functional protease-chaperone DegP12/24. The newly formed cage exhibits the characteristics of a proteolytic folding chamber, shredding those proteins that are severely misfolded while stabilizing and protecting proteins present in their native state. Isolation of native DegP complexes with folded outer membrane proteins (OMPs) highlights the importance of DegP in OMP biogenesis. The encapsulated OMP beta-barrel is significantly stabilized in the hydrophobic chamber of DegP12/24 and thus DegP seems to employ a reciprocal mechanism to those chaperones assisting the folding of water soluble proteins via polar interactions. In addition, we discuss in this review similarities to other complex proteolytic machines that, like DegP, are under control of a substrate-induced or stress-induced oligomer conversion.

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Structure and assembly of pore-forming proteins.

Publication Date: 2010 Feb 19 PMID: 20172710
Authors: Iacovache, I. - Bischofberger, M. - van der Goot, F. G.
Journal: Curr Opin Struct Biol

Pore-forming proteins (PFPs), involved in host-pathogen interactions, are produced as soluble, generally monomeric, proteins. To convert from the soluble to the transmembrane form, PFPs assemble, in the vicinity of the target membrane, into ring-like structures, which expose sufficient hydrophobicity to drive spontaneous bilayer insertion. Recent findings have highlighted two interesting aspects: (1) that pores form via similar overall mechanisms even if originating from vastly different structures and (2) specific folds found in PFPs can be found in widely different organisms, as distant as prokaryotes and mammals, highlighting that pore formation is an ancient form of attack that has been remarkably conserved.

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Targeting biomolecular flexibility with metadynamics.

Publication Date: 2010 Feb 18 PMID: 20171876
Authors: Leone, V. - Marinelli, F. - Carloni, P. - Parrinello, M.
Journal: Curr Opin Struct Biol

Metadynamics calculations allow investigating structure, plasticity, and energetics in a variety of biological processes spanning from molecular docking to protein folding. Recent theoretical developments have led to applications to increasingly complex systems and processes stepping up the biological relevance of the problem solved. Here, after summarizing recent technical advances and applications, we give a perspective of the method as a tool for enzymology and for the prediction of NMR and other spectroscopic data.

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Nuclear export complexes in the frame.

Publication Date: 2010 Feb 18 PMID: 20171875
Authors: Cook, A. G. - Conti, E.
Journal: Curr Opin Struct Biol

Protein and RNA molecules are exchanged between the nucleus and cytoplasm by members of the karyopherin beta family of transport factors. Karyopherins adopt a modular HEAT-repeat architecture and are regulated by the GTPase Ran. RanGTP acts as a signal for the nuclear compartment, dissociating molecular cargo from karyopherins that mediate nuclear import and promoting cargo uptake on those mediating nuclear export. After unraveling the mechanisms of nuclear import factors, structural studies have recently provided tremendous insights into nuclear export. The impact of RanGTP binding on the karyopherins ranges from large, global conformational changes to local, allosteric effects. A theme emerges where cargo recognition provides a molecular surveillance mechanism to prevent the transport of macromolecules in an inappropriate state.

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An intracellular traffic jam: Fc receptor-mediated transport of immunoglobulin G.

Publication Date: 2010 Feb 18 PMID: 20171874
Authors: Tesar, D. B. - Bjorkman, P. J.
Journal: Curr Opin Struct Biol

Recent advances in imaging techniques along with more powerful in vitro and in vivo models of receptor-mediated ligand transport are facilitating advances in our understanding of how cells efficiently direct receptors and their cargo to target destinations within the cytoplasm and at the plasma membrane. Specifically, light and 3D electron microscopy studies examining the trafficking behavior of the neonatal Fc receptor (FcRn), a transport receptor for immunoglobulin G (IgG), have given us new insights into the dynamic interplay between the structural components of the cytosolic trafficking machinery, its protein regulators, and the receptors it directs to various locations within the cell. These studies build upon previous biochemical characterizations of FcRn transport and are allowing us to begin formulation of a more complete model for the intracellular trafficking of receptor-ligand complexes.

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Models of macromolecular crowding effects and the need for quantitative comparisons with experiment.

Publication Date: 2010 Feb 16 PMID: 20167475
Authors: Elcock, A. H.
Journal: Curr Opin Struct Biol

In recent years significant effort has been devoted to exploring the potential effects of macromolecular crowding on protein folding and association phenomena. Theoretical calculations and molecular simulations have, in particular, been exploited to describe aspects of protein behavior in crowded and confined conditions and many aspects of the simulated behavior have reflected, at least at a qualitative level, the behavior observed in experiments. One major and immediate challenge for the theorists is to now produce models capable of making quantitatively accurate predictions of in vitro behavior. A second challenge is to derive models that explain results obtained from experiments performed in vivo, the results of which appear to call into question the assumed dominance of excluded-volume effects in vivo.

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