Current Opinion in Structural Biology

Cradle-loop barrels and the concept of metafolds in protein classification by natural descent.

Publication Date: 2008 May 3 PMID: 18457946
Authors: Alva, V. - Koretke, K. K. - Coles, M. - Lupas, A. N.
Journal: Curr Opin Struct Biol

Current classification systems for protein structure show many inconsistencies both within and between systems. The metafold concept was introduced to identify fold similarities by consensus and thus provide a more unified view of fold space. Using cradle-loop barrels as an example, we propose to use the metafold as the next hierarchical level above the fold, encompassing a group of topologically related folds for which a homologous relationship has been substantiated. We see this as an important step on the way to a classification of proteins by natural descent.

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Evolution and dynamics of protein interactions and networks.

Publication Date: 2008 Apr 28 PMID: 18448325
Authors: Levy, E. D. - Pereira-Leal, J. B.
Journal: Curr Opin Struct Biol

The central role of protein-protein interactions (PPIs) in biology has stimulated colossal efforts to identify thousands of them in several organisms. The resulting PPI maps are commonly represented as graphs, where nodes denote proteins and edges represent physical interactions. However, the methods used to generate PPI data on a large scale do not readily allow one to discriminate features such as interaction strength (affinity), type (protein-protein or protein-peptide interaction) or spatiotemporal existence (where and when the proteins are present and interact). Yet, in recent years, a number of studies have tackled these limitations by projecting additional information onto PPIs, revealing novel properties in terms of their evolution and dynamics. In this review we examine these properties both at the binary interaction level and at the network level. We suggest that the diverse and sometimes contradictory results described by different research groups are mostly due to incomplete data coverage and limited data types. Finally, we discuss recently developed methods that will improve this picture in the future.

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Core principles of intramembrane proteolysis: comparison of rhomboid and site-2 family proteases.

Publication Date: 2008 Apr 25 PMID: 18440799
Authors: Urban, S. - Shi, Y.
Journal: Curr Opin Struct Biol

Cleavage of proteins within their membrane-spanning segments is an ancient regulatory mechanism that has evolved to control a myriad of cellular processes in all forms of life. Although three mechanistic families of enzymes have been discovered that catalyze hydrolysis within the water-excluding environment of the membrane, how they achieve this improbable reaction has been both a point of controversy and skepticism. The crystal structures of rhomboid and site-2 protease, two different classes of intramembrane proteases, have been solved recently. Combined with current biochemical analyses, this advance provides an unprecedented view of how nature has solved the problem of facilitating hydrolysis within membranes in two independent instances. We focus on detailing the similarities between these unrelated enzymes to define core biochemical principles that govern this conserved regulatory mechanism.

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Progress and challenges in protein structure prediction.

Publication Date: 2008 Apr 22 PMID: 18436442
Authors: Zhang, Y.
Journal: Curr Opin Struct Biol

Depending on whether similar structures are found in the PDB library, the protein structure prediction can be categorized into template-based modeling and free modeling. Although threading is an efficient tool to detect the structural analogs, the advancements in methodology development have come to a steady state. Encouraging progress is observed in structure refinement which aims at drawing template structures closer to the native; this has been mainly driven by the use of multiple structure templates and the development of hybrid knowledge-based and physics-based force fields. For free modeling, exciting examples have been witnessed in folding small proteins to atomic resolutions. However, predicting structures for proteins larger than 150 residues still remains a challenge, with bottlenecks from both force field and conformational search.

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