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Drew T Wagner, Jia Zeng, Constance B Bailey, Darren C Gay, Fang Yuan, Hannah R Manion, Adrian T Keatinge-Clay
In an effort to uncover the structural motifs and biosynthetic logic of the relatively uncharacterized trans-acyltransferase polyketide synthases, we have begun the dissection of the enigmatic dehydrating bimodules common in these enzymatic assembly lines. We report the 1.98 Å resolution structure of a ketoreductase (KR) from the first half of a type A dehydrating bimodule and the 2.22 Å resolution structure of a dehydratase (DH) from the second half of a type B dehydrating bimodule. The KR, from the third module of the bacillaene synthase, and the DH, from the tenth module of the difficidin synthase, possess features not observed in structurally characterized homologs...
June 7, 2017: Structure
Johannes Thoma, Noah Ritzmann, Dominik Wolf, Estefania Mulvihill, Sebastian Hiller, Daniel J Müller
Upon mechanical pulling at either terminal end, β barrel outer membrane proteins stepwise unfold β strands or β hairpins until entirely extracted from the membrane. This unique unfolding pathway has been described for β barrels comprising 8, 14, or 22 β strands. Here we mechanically unfold the 18-stranded β barrel outer membrane protein LamB from Escherichia coli. We find that its mechanical unfolding pathway is shaped by the stepwise unfolding of β hairpins. However, we also observe that β hairpins can unfold groupwise...
June 6, 2017: Structure
Marios Frantzeskos Sardis, Alexandra Tsirigotaki, Katerina Elias Chatzi, Athina George Portaliou, Giorgos Gouridis, Spyridoula Karamanou, Anastassios Economou
Most bacterial secretory proteins destined beyond the plasma membrane are secreted post-translationally by the Sec translocase. In the first step of translocation, preproteins are targeted for binding to their 2-site receptor SecA, the peripheral ATPase subunit of the translocase. We now reveal that secretory preproteins use a dual-key mechanism to bridge the signal peptide and mature domain receptor sites and cooperatively enhance their affinities. Docking of targeting-competent mature domains requires that their extensive disorder is finely tuned...
June 5, 2017: Structure
John P O'Donnell, Richard B Cooley, Carolyn M Kelly, Kurt Miller, Olaf S Andersen, Radda Rusinova, Holger Sondermann
The endoplasmic reticulum (ER) forms a branched, dynamic membrane tubule network that is vital for cellular function. Branching arises from membrane fusion facilitated by the GTPase atlastin (ATL). Many metazoan genomes encode for three ATL isoforms that appear to fulfill partially redundant function despite differences in their intrinsic GTPase activity and localization within the ER; however, the underlying mechanistic differences between the isoforms are poorly understood. Here, we identify discrete temporal steps in the catalytic cycle for the two most dissimilar isoforms, ATL1 and ATL3, revealing an overall conserved progression of molecular events from nucleotide binding and hydrolysis to ATL dimerization and phosphate release...
May 31, 2017: Structure
Deepankar Gahloth, Colin Levy, Louise Walker, Lydia Wunderley, A Paul Mould, Sandra Taylor, Philip Woodman, Lydia Tabernero
SARA and endofin are endosomal adaptor proteins that drive Smad phosphorylation by ligand-activated transforming growth factor β/bone morphogenetic protein (TGFβ/BMP) receptors. We show in this study that SARA and endofin also recruit the tumor supressor HD-PTP, a master regulator of endosomal sorting and ESCRT-dependent receptor downregulation. High-affinity interactions occur between the SARA/endofin N termini, and the conserved hydrophobic region in the HD-PTP Bro1 domain that binds CHMP4/ESCRT-III. CHMP4 engagement is a universal feature of Bro1 proteins, but SARA/endofin binding is specific to HD-PTP...
May 30, 2017: Structure
Thomas R Lane, Elaine Fuchs, Kevin C Slep
Spectraplakins are large molecules that cross-link F-actin and microtubules (MTs). Mutations in spectraplakins yield defective cell polarization, aberrant focal adhesion dynamics, and dystonia. We present the 2.8 Å crystal structure of the hACF7 EF1-EF2-GAR MT-binding module and delineate the GAR residues critical for MT binding. The EF1-EF2 and GAR domains are autonomous domains connected by a flexible linker. The EF1-EF2 domain is an EFβ-scaffold with two bound Ca(2+) ions that straddle an N-terminal α helix...
May 30, 2017: Structure
Kathrin Wiebke Schulte, Edward Green, Annabel Wilz, Michael Platten, Oliver Daumke
The aryl hydrocarbon receptor (AHR) and the AHR nuclear translocator (ARNT) constitute a heterodimeric basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain containing transcription factor with central functions in development and cellular homeostasis. AHR is activated by xenobiotics, notably dioxin, as well as by exogenous and endogenous metabolites. Modulation of AHR activity holds promise for the treatment of diseases featuring altered cellular homeostasis, such as cancer or autoimmune disorders. Here, we present the crystal structure of a heterodimeric AHR:ARNT complex containing the PAS A and bHLH domain bound to its target DNA...
May 30, 2017: Structure
Warintra Pitsawong, Chad A Haynes, Ronald L Koder, David W Rodgers, Anne-Frances Miller
Nitroreductase (NR) from Enterobacter cloacae reduces diverse nitroaromatics including herbicides, explosives, and prodrugs, and holds promise for bioremediation, prodrug activation, and enzyme-assisted synthesis. We solved crystal structures of NR complexes with bound substrate or analog for each of its two half-reactions. We complemented these with kinetic isotope effect (KIE) measurements elucidating H-transfer steps essential to each half-reaction. KIEs indicate hydride transfer from NADH to the flavin consistent with our structure of NR with the NADH analog nicotinic acid adenine dinucleotide (NAAD)...
May 30, 2017: Structure
David Albesa-Jové, Javier Romero-García, Enea Sancho-Vaello, F-Xabier Contreras, Ane Rodrigo-Unzueta, Natalia Comino, Ana Carreras-González, Pedro Arrasate, Saioa Urresti, Xevi Biarnés, Antoni Planas, Marcelo E Guerin
Glycosyltransferases (GTs) play a central role in nature. They catalyze the transfer of a sugar moiety to a broad range of acceptor substrates. GTs are highly selective enzymes, allowing the recognition of subtle structural differences in the sequences and stereochemistry of their sugar and acceptor substrates. We report here a series of structural snapshots of the reaction center of the retaining glucosyl-3-phosphoglycerate synthase (GpgS). During this sequence of events, we visualize how the enzyme guides the substrates into the reaction center where the glycosyl transfer reaction takes place, and unveil the mechanism of product release, involving multiple conformational changes not only in the substrates/products but also in the enzyme...
May 26, 2017: Structure
Hila Sameach, Aya Narunsky, Salome Azoulay-Ginsburg, Lada Gevorkyan-Aiapetov, Yonathan Zehavi, Yoni Moskovitz, Tamar Juven-Gershon, Nir Ben-Tal, Sharon Ruthstein
CueR (Cu export regulator) is a metalloregulator protein that "senses" Cu(I) ions with very high affinity, thereby stimulating DNA binding and the transcription activation of two other metalloregulator proteins. The crystal structures of CueR when unbound or bound to DNA and a metal ion are very similar to each other, and the role of CueR and Cu(I) in initiating the transcription has not been fully understood yet. Using double electron-electron resonance (DEER) measurements and structure modeling, we investigate the conformational changes that CueR undergoes upon binding Cu(I) and DNA in solution...
May 26, 2017: Structure
Mohit Misra, Maximilian Kuhn, Mark Löbel, Heeseon An, Alexander V Statsyuk, Christoph Sotriffer, Hermann Schindelin
Targeting the activating enzymes (E1) of ubiquitin (Ub) and ubiquitin-like modifiers (Ubls) has emerged as a promising anti-cancer strategy, possibly overcoming the ineffectiveness of proteasome inhibitors against solid tumors. Here, we report crystal structures of the yeast ubiquitin E1 (Uba1) with three adenosyl sulfamate inhibitors exhibiting different E1 specificities, which are all covalently linked to ubiquitin. The structures illustrate how the chemically diverse inhibitors are accommodated within the adenylation active site...
May 26, 2017: Structure
Rebecca M Pollet, Emma H D'Agostino, William G Walton, Yongmei Xu, Michael S Little, Kristen A Biernat, Samuel J Pellock, Loraine M Patterson, Benjamin C Creekmore, Hanna N Isenberg, Rohini R Bahethi, Aadra P Bhatt, Jian Liu, Raad Z Gharaibeh, Matthew R Redinbo
Microbiome-encoded β-glucuronidase (GUS) enzymes play important roles in human health by metabolizing drugs in the gastrointestinal (GI) tract. The numbers, types, and diversity of these proteins in the human GI microbiome, however, remain undefined. We present an atlas of GUS enzymes comprehensive for the Human Microbiome Project GI database. We identify 3,013 total and 279 unique microbiome-encoded GUS proteins clustered into six unique structural categories. We assign their taxonomy, assess cellular localization, reveal the inter-individual variability within the 139 individuals sampled, and discover 112 novel microbial GUS enzymes...
May 25, 2017: Structure
Teresa A F Cardote, Morgan S Gadd, Alessio Ciulli
Cullin RING E3 ubiquitin ligases (CRLs) function in the ubiquitin proteasome system to catalyze the transfer of ubiquitin from E2 conjugating enzymes to specific substrate proteins. CRLs are large dynamic complexes and attractive drug targets for the development of small-molecule inhibitors and chemical inducers of protein degradation. The atomic details of whole CRL assembly and interactions that dictate subunit specificity remain elusive. Here we present the crystal structure of a pentameric CRL2(VHL) complex, composed of Cul2, Rbx1, Elongin B, Elongin C, and pVHL...
June 6, 2017: Structure
Ishutesh Jain, Phong T Tran
Microtubule (MT) dynamics are regulated by a plethora of microtubule-associated proteins (MAPs). An important MT regulator is the end binding protein EB, which serves as a scaffold to recruit other MAPs to MT plus ends. In this issue of Structure, Kumar et al. (2017) describe LxxPTPh, a new linear sequence motif that can bind EBs. The finding opens up the possibility of discovering new MT regulators.
June 6, 2017: Structure
Guy Hervé
The CAD complex catalyzes the first four reactions of the pyrimidine biosynthetic pathway. CAD exhibits allosteric regulaton, both negative and positive, covalent regulation by phosphorylation, and metabolite channeling. In this issue of Structure, Moreno-Morcillo et al. (2017) show that the dihydroorotase domain plays a crucial role in the establishment of the quaternary structure of this complex.
June 6, 2017: Structure
Karen M Dunkerley, Gary S Shaw
The three distinct types of E3 ubiquitin ligases, RING, HECT, and RBR, employ different modes of ubiquitin transfer including E2∼Ub conjugate type and conformation. In this issue of Structure, Dove et al. (2017) provide a structural rationale for the preference and conformation of the UbcH7∼Ub conjugate by the RBR E3 ligase HHARI.
June 6, 2017: Structure
María Moreno-Morcillo, Araceli Grande-García, Alba Ruiz-Ramos, Francisco Del Caño-Ochoa, Jasminka Boskovic, Santiago Ramón-Maiques
CAD, the multifunctional protein initiating and controlling de novo biosynthesis of pyrimidines in animals, self-assembles into ∼1.5 MDa hexamers. The structures of the dihydroorotase (DHO) and aspartate transcarbamoylase (ATC) domains of human CAD have been previously determined, but we lack information on how these domains associate and interact with the rest of CAD forming a multienzymatic unit. Here, we prove that a construct covering human DHO and ATC oligomerizes as a dimer of trimers and that this arrangement is conserved in CAD-like from fungi, which holds an inactive DHO-like domain...
June 6, 2017: Structure
Anil Kumar, Cristina Manatschal, Ankit Rai, Ilya Grigoriev, Miriam Steiner Degen, Rolf Jaussi, Ines Kretzschmar, Andrea E Prota, Rudolf Volkmer, Richard A Kammerer, Anna Akhmanova, Michel O Steinmetz
Microtubule plus-end tracking proteins (+TIPs) are involved in virtually all microtubule-based processes. End-binding (EB) proteins are considered master regulators of +TIP interaction networks, since they autonomously track growing microtubule ends and recruit a plethora of proteins to this location. Two major EB-interacting elements have been described: CAP-Gly domains and linear SxIP sequence motifs. Here, we identified LxxPTPh as a third EB-binding motif that enables major +TIPs to interact with EBs at microtubule ends...
June 6, 2017: Structure
Zachary Frazier, Min Xu, Frank Alber
Cryo-electron tomography (cryo-ET) captures the 3D electron density distribution of macromolecular complexes in close to native state. With the rapid advance of cryo-ET acquisition technologies, it is possible to generate large numbers (>100,000) of subtomograms, each containing a macromolecular complex. Often, these subtomograms represent a heterogeneous sample due to variations in the structure and composition of a complex in situ form or because particles are a mixture of different complexes. In this case subtomograms must be classified...
June 6, 2017: Structure
Katja K Dove, Jennifer L Olszewski, Luigi Martino, David M Duda, Xiaoli S Wu, Darcie J Miller, Katherine H Reiter, Katrin Rittinger, Brenda A Schulman, Rachel E Klevit
RING-between-RING (RBR) E3s contain RING1 domains that are structurally similar yet mechanistically distinct from canonical RING domains. Both types of E3 bind E2∼ubiquitin (E2∼Ub) via their RINGs but canonical RING E3s promote closed E2∼Ub conformations required for direct Ub transfer from the E2 to substrate, while RBR RING1s promote open E2∼Ub to favor Ub transfer to the E3 active site. This different RING/E2∼Ub conformation determines its direct target, which for canonical RING E3s is typically a substrate or substrate-linked Ub, but is the E3 active-site cysteine in the case of RBR-type E3s...
June 6, 2017: Structure
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