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AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis in mammals. AMP is believed to control the activity of AMPK by binding to the γ subunit of this heterotrimeric enzyme. This subunit contains two Bateman domains, each of which is composed of a tandem pair of cystathionine β-synthase (CBS) motifs. No structural information is currently available on this subunit, and the...
In this issue of Structure, Bashton and Chothia (2007) examine in detail the functions of selected domains within proteins both when they are alone and when in combination with others. Domain function is relevant to molecular evolution and to annotation of proteins known only by sequence.
SR protein kinase 1 (SRPK1) is a constitutively active kinase, which processively phosphorylates multiple serines within its substrates, ASF/SF2. We describe crystallographic, molecular dynamics, and biochemical results that shed light on how SRPK1 preserves its constitutive active conformation. Our structure reveals that unlike other known active kinase structures, the activation loop remains in...
Hepatocyte nuclear factor-6 (HNF-6), a liver-enriched transcription factor, controls the development of various tissues, such as the pancreas and liver, and regulates the expression of several hepatic genes. This protein belongs to the ONECUT class of homeodomain proteins and contains a bipartite DNA-binding domain composed of a single cut domain and a characteristic homeodomain. This transcription...
Prefoldin (PFD) is a molecular chaperone that stabilizes and then delivers unfolded proteins to a chaperonin for facilitated folding. The PFD hexamer has undergone an evolutionary change in subunit composition, from two PFDα and four PFDβ subunits in archaea to six different subunits (two α-like and four β-like subunits) in eukaryotes. Here, we show by electron microscopy that PFD from the archaeum...
An increasing number of structural studies of large macromolecular complexes, both in X-ray crystallography and cryo-electron microscopy, have resulted in intermediate-resolution (5–10 Å) density maps. Despite being limited in resolution, significant structural and functional information may be extractable from these maps. To aid in the analysis and annotation of these complexes, we have developed...
The Rieske [2Fe-2S] iron-sulfur protein of cytochrome bc 1 functions as the initial electron acceptor in the rate-limiting step of the catalytic reaction. Prior studies have established roles for a number of conserved residues that hydrogen bond to ligands of the [2Fe-2S] cluster. We have constructed site-specific variants at two of these residues, measured their thermodynamic and functional...
A high-resolution cryo-EM reconstruction of a ribosome-bound dicistrovirus IRES (Schüler et al., 2006) and the crystal structure of its ribosome binding domain (Pfingsten et al., 2006) provide new insights into an exceptional eukaryotic translation mechanism.
Packaging of genetic material inside a capsid is one of the major processes in the lifecycle of bacteriophages. To establish the basic principles of packing double-stranded DNA into a phage, we present a low-resolution model of bacteriophage ϕ29 and report simulations of DNA packaging. The simulations show excellent agreement with available experimental data, including the forces of packaging and...
Actin structure is of intense interest in biology due to its importance in cell function and motility mediated by the spatial and temporal regulation of actin monomer-filament interconversions in a wide range of developmental and disease states. Despite this interest, the structure of many functionally important actin forms has eluded high-resolution analysis. Due to the propensity of actin monomers...
Natural proteins fold to a unique, thermodynamically dominant state. Modeling of the folding process and prediction of the native fold of proteins are two major unsolved problems in biophysics. Here, we show successful all-atom ab initio folding of a representative diverse set of proteins by using a minimalist transferable-energy model that consists of two-body atom-atom interactions, hydrogen bonding,...
During evolution, many new proteins have been formed by the process of gene duplication and combination. The genes involved in this process usually code for whole domains. Small proteins contain one domain; medium and large proteins contain two or more domains. We have compared homologous domains that occur in both one-domain proteins and multidomain proteins. We have determined (1) how the functions...
α/β-Knotted proteins are an extraordinary example of biological self-assembly; they contain a deep topological trefoil knot formed by the backbone polypeptide chain. Evidence suggests that all are dimeric and function as methyltransferases, and the deep knot forms part of the active site. We investigated the significance of the dimeric structure of the α/β-knot protein, YibK, from Haemophilus influenzae...
The recent determination of protein structures with knots in their backbone topology has defied previous conventional wisdom. How proteins can fold with a knot is an intriguing question that has been explored for YibK from Haemophilus influenzae in this issue of Structure (Mallam and Jackson, 2007a).
Gankyrin is an oncoprotein commonly overexpressed in most hepatocellular carcinomas. Gankyrin interacts with S6 ATPase of the 19S regulatory particle of the 26S proteasome and enhances the degradation of the tumor suppressors pRb and p53. Here, we report the structure of gankyrin in complex with the C-terminal domain of S6 ATPase. Almost all of the seven ankyrin repeats of gankyrin interact, through...
Asf1 is a histone chaperone that favors histone H3/H4 assembly and disassembly. We solved the structure of the conserved domain of human ASF1A in complex with the C-terminal helix of histone H3 using nuclear magnetic resonance spectroscopy. This structure is fully compatible with an association of ASF1 with the heterodimeric form of histones H3/H4. In our model, ASF1 substitutes for the second H3/H4...
Hydrogen exchange experiments provide detailed information about the local stability and the solvent accessibility of different regions of the structures of folded proteins, protein complexes, and amyloid fibrils. We introduce an approach to predict protection factors from hydrogen exchange in proteins based on the knowledge of their amino acid sequences without the inclusion of any additional structural...
In this issue of Structure, Yokoyama and coworkers report a complex structure that reveals how gankyrin binds to another subunit of the 26S proteasome and that has implications for its interactions with phosphorylation and ubiquitylation targeting factors as well as tumor suppressor substrates (Nakamura et al., 2007).
Hydrophobic residues outside the active site of HIV-1 protease frequently mutate in patients undergoing protease inhibitor therapy; however, the mechanism by which these mutations confer drug resistance is not understood. From analysis of molecular dynamics simulations, 19 core hydrophobic residues appear to facilitate the conformational changes that occur in HIV-1 protease. The hydrophobic core residues...
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