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How transmembrane β-barrel proteins insert and fold into membranes and by which factors they destabilize, unfold, and misfold represents a field of intense studies. Here, we use single-molecule force spectroscopy to characterize the un- and refolding of the ferric hydroxamate uptake receptor (FhuA), which is one of the largest β-barrel proteins of the outer membrane of Escherichia coli. Applied to...
[NiFe] hydrogenase maturation represents one of the most dynamic and sophisticated processes in metallocenter assembly. The Fe(CN) 2 CO moiety of [NiFe] hydrogenases is assembled via unknown transient interactions among specific maturation proteins HypC (metallochaperone), HypD (redox protein), and HypE (cyanide synthesis/donor). Here, we report the structures of the HypC-HypD and HypC-HypD-HypE...
HCN channels and their modulation by cAMP play a key role in cardiac pacemaking. In this issue of Structure, Xu and colleagues reveal that an arrhythmia-causing mutation of an HCN channel weakens cAMP binding to the channel by altering the local structure of its entry-exit pathway.
RCK domains control activity of a variety of K + channels and transporters through binding of cytoplasmic ligands. To gain insight toward mechanisms of RCK domain activation, we solved the structure of the RCK domain from the Ca 2+ -gated K + channel, MthK, bound with Ba 2+ , at 3.1 Å resolution. The Ba 2+ -bound RCK domain was assembled as an octameric gating...
c-Jun N-terminal (JNK) family kinases have a common peptide-docking site used by upstream activating kinases, substrates, scaffold proteins, and phosphatases, where the ensemble of bound proteins determines signaling output. Although there are many JNK structures, little is known about mechanisms of allosteric regulation between the catalytic and peptide-binding sites, and the activation loop, whose...
In this issue of Structure, Bunney and colleagues use a combination of NMR, SAXS, crystallography, ITC, and biochemical methods to elucidate, in molecular detail, the sequence of events causing receptor-mediated activation of phospholipase C-γ 1 by protein tyrosine phosphorylation.
Facilitated binding of p53 to DNA by high mobility group B1 (HMGB1) may involve interaction between the N-terminal region of p53 and the high mobility group (HMG) boxes, as well as HMG-induced bending of the DNA. Intramolecular shielding of the boxes by the HMGB1 acidic tail results in an unstable complex with p53 until the tail is truncated to half its length, at which point the A box, proposed to...
Single-particle electron microscopy (EM) is a powerful tool for studying the structures of large biological molecules. However, the achievable resolution does not always allow for direct recognition of individual protein domains. Labels that can be visualized by EM have been developed for protein termini, but tagging internal domains remains a challenge. We describe a robust strategy for determining...
Cryo-electron microscopy (cryo-EM) is a powerful technique for 3D structure determination of protein complexes by averaging information from individual molecular images. The resolutions that can be achieved with single-particle cryo-EM are frequently limited by inaccuracies in assigning molecular orientations based solely on 2D projection images. Tomographic data collection schemes, however, provide...
Recognition of ubiquitin and polyubiquitin chains by ubiquitin-binding domains (UBDs) is vital for ubiquitin-mediated signaling pathways. The endoplasmic reticulum resident RING finger ubiquitin ligase (E3) gp78 regulates critical proteins via the ubiquitin-proteasome system to maintain cellular homeostasis and includes a UBD known as the CUE domain, which is essential for function. A probable role...
Neisseria gonorrhoeae is an obligate human pathogen that can escape immune surveillance through antigenic variation of surface structures such as pili. A G-quadruplex-forming (G4) sequence (5′-G 3 TG 3 TTG 3 TG 3 ) located upstream of the N. gonorrhoeae pilin expression locus (pilE) is necessary for initiation of pilin antigenic variation, a recombination-based, high-frequency,...
Nonsense-mediated mRNA decay (NMD) is an important mRNA surveillance system, and human PNRC2 protein mediates the link between mRNA surveillance and decapping. However, the mechanism by which PNRC2 interacts with the mRNA surveillance machinery and stimulates NMD is unknown. Here, we present the crystal structure of Dcp1a in complex with PNRC2. The proline-rich region of PNRC2 is bound to the EVH1...
In vertebrates ecto-5′-nucleotidase (e5NT) catalyzes the hydrolysis of extracellular AMP to adenosine and represents the major control point for extracellular adenosine levels. Due to its pivotal role for activation of P1 adenosine receptors, e5NT has emerged as an appealing drug target for treatment of inflammation, chronic pain, hypoxia, and cancer. Crystal structures of the dimeric human e5NT reveal...
RIG-I is a cytosolic sensor of viral RNA, comprised of two N-terminal CARDs followed by helicase and C-terminal regulatory domains (helicase-CTD). Viral RNA binds to the helicase-CTD and “exposes” the CARDs for downstream signaling. The role of the second CARD (CARD2) is essential as RIG-I activation requires dephosphorylation of Thr170 followed by ubiquitination at Lys172. Here, we present the solution...
Repair of DNA double-strand breaks (DSBs) is essential for cell survival and maintaining genome integrity. DSBs are repaired in a stepwise manner by homologous recombination. Here, we focused on the early steps of DSB repair, including DSB recognition, which is still only poorly understood. In prokaryotes, this process has been proposed to involve the RecN protein, a member of the structural maintenance...
Multidomain proteins incorporating interaction domains are central to regulation of cellular processes. The elucidation of structural organization and mechanistic insights into many of these proteins, however, remain challenging due to their inherent flexibility. Here, we describe the organization and function of four interaction domains in PLCγ1 using a combination of structural biology and biochemical...
In this issue of Structure, Zhang and colleagues present the structure of the Ego3 dimer, demonstrating that dimerization is an obligate prerequisite in amino acid-induced TORC1 activation.
The yeast EGO complex, consisting of Gtr1, Gtr2, Ego1, and Ego3, localizes to the endosomal and vacuolar membranes and plays a pivotal role in cell growth and autophagy regulation through relaying amino acid signals to activate TORC1. Here, we report the crystal structures of a wild-type and a mutant form of Saccharomyces cerevisiae Ego3. Ego3 assumes a homodimeric structure similar to that of the...
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