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Oligosaccharyl transferase (OT) catalyzes the transfer of a lipid-linked oligosaccharide to the nascent polypeptide emerging from the translocon. Currently, there is no structural information on the membrane-embedded OT complex, which consists of eight different polypeptide chains. We report a 12 Å resolution cryo-electron microscopy structure of OT from yeast. We mapped the locations of four essential...
Blood clots must be stiff to stop hemorrhage yet elastic to buffer blood's shear forces. Upsetting this balance results in clot rupture and life-threatening thromboembolism. Fibrin, the main component of a blood clot, is formed from molecules of fibrinogen activated by thrombin. Although it is well known that fibrin possesses considerable elasticity, the molecular basis of this elasticity is unknown...
Systematic efforts to understand membrane protein stability under a variety of different solution conditions are not widely available for membrane proteins, mainly due to technical problems stemming from the presence of detergents necessary to keep the proteins in the solubilized state and the background that such detergents usually generate during biophysical characterization. In this report, we...
Colicins kill Escherichia coli after translocation across the outer membrane. Colicin N displays an unusually simple translocation pathway, using the outer membrane protein F (OmpF) as both receptor and translocator. Studies of this binary complex may therefore reveal a significant component of the translocation pathway. Here we show that, in 2D crystals, colicin is found outside the porin trimer,...
The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) regulates the nonhomologous end joining pathway for repair of double-stranded DNA (dsDNA) breaks. Here, we present a 7Å resolution structure of DNA-PKcs determined by cryo-electron microscopy single-particle reconstruction. This structure is composed of density rods throughout the molecule that are indicative of α helices and reveals structural...
The 1.1 MDa cell-wall-associated adhesion protein of staphylococci, Ebh, consists of several distinct regions, including a large central region with 52 imperfect repeats of 126 amino acid residues. We investigated the structure of this giant molecule by X-ray crystallography, circular dichroism (CD) spectrometry, and small-angle X-ray scattering (SAXS). The crystal structure of two repeats showed...
Qiu et al. (2008) add new weight to the very highly detailed understanding of how extracellular ligand binding-induced dimerization of a receptor tyrosine kinase is first manifested inside the cell.
β-catenin plays essential roles in cell adhesion and Wnt signaling, while deregulation of β-catenin is associated with multiple diseases including cancers. Here, we report the crystal structures of full-length zebrafish β-catenin and a human β-catenin fragment that contains both the armadillo repeat and the C-terminal domains. Our structures reveal that the N-terminal region of the C-terminal domain,...
In this issue of Structure, the Stewart laboratory and their collaborators have provided a markedly improved cryo-EM reconstruction of DNA-PKcs (Williams et al., 2008). The new level of detail heightens interest in integrating the understanding of nonhomologous DNA end joining.
DNA topoisomerases resolve DNA topological problems created during transcription, replication, and recombination. These ubiquitous enzymes are essential for cell viability and are highly potent targets for the development of antibacterial and antitumoral drugs. Type II enzymes catalyze the transfer of a DNA duplex through another one in an ATP-dependent mechanism. Because of its small size and sensitivity...
Peroxisomal carbonyl reductase (PerCR), a tetrameric enzyme, enters peroxisomes when expressed in human cells, but not when PerCR tetramers are introduced into these cells. The PerCR crystal structure (Tanaka et al., 2008) yields insights that explain these data.
The methylation of mammalian DNA, primarily at CpG dinucleotides, has long been recognized to play a major role in controlling gene expression, among other functions. Given their importance, it is surprising how many basic questions remain to be answered about the proteins responsible for this methylation and for coordination with the parallel chromatin-marking system that operates at the level of...
A strong interplay between the voltage-sensor domain (VSD) and the pore domain (PD) underlies voltage-gated channel functions. In a few voltage-sensitive proteins, the VSD has been shown to function without a canonical PD, although its structure and oligomeric state remain unknown. Here, using EPR spectroscopy, we show that the isolated VSD of KvAP can remain monomeric in a reconstituted bilayer and...
β-catenin is remarkably multifunctional, acting in adhesion, cytoskeletal regulation, and Wnt signaling. In this issue, Xing et al. (2008) present the full-length structure of β-catenin, providing a clearer picture of how these terminal regions modulate β-catenin activities.
Presynaptic neurexins (NRXs) bind to postsynaptic neuroligins (NLs) to form Ca 2+ -dependent complexes that bridge neural synapses. β-NRXs bind NLs through their LNS domains, which contain a single site of alternative splicing (splice site 4) giving rise to two isoforms: +4 and Δ. We present crystal structures of the Δ isoforms of the LNS domains from β-NRX1 and β-NRX2, crystallized in the...
The diacylglycerol kinase (DGK) enzymes function as regulators of intracellular signaling by altering the levels of the second messengers, diacylglycerol and phosphatidic acid. The DGK δ and η isozymes possess a common protein-protein interaction module known as a sterile α-motif (SAM) domain. In DGK δ, SAM domain self-association inhibits the translocation of DGK δ to the plasma membrane. Here we...
Neurexins and neuroligins play an essential role in synapse function, and their alterations are linked to autistic spectrum disorder. Interactions between neurexins and neuroligins regulate inhibitory and excitatory synaptogenesis in vitro through a “splice-insert signaling code.” In particular, neurexin 1β carrying an alternative splice insert at site SS#4 interacts with neuroligin 2 (found predominantly...
In this work, we employ single-particle electron cryo-microscopy (cryo-EM) to reconstruct GroEL to ∼4 Å resolution with both D7 and C7 symmetry. Using a newly developed skeletonization algorithm and secondary structure element identification in combination with sequence-based secondary structure prediction, we demonstrate that it is possible to achieve a de novo Cα trace directly from a cryo-EM reconstruction...
HER4/ErbB4 is a ubiquitously expressed member of the EGF/ErbB family of receptor tyrosine kinases that is essential for normal development of the heart, nervous system, and mammary gland. We report here crystal structures of the ErbB4 kinase domain in active and lapatinib-inhibited forms. Active ErbB4 kinase adopts an asymmetric dimer conformation essentially identical to that observed to be important...
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