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Franziska Bleichert, Alexander Leitner, Ruedi Aebersold, Michael R Botchan, James M Berger
In eukaryotes, the heterohexameric origin recognition complex (ORC) coordinates replication onset by facilitating the recruitment and loading of the minichromosome maintenance 2-7 (Mcm2-7) replicative helicase onto DNA to license origins. Drosophila ORC can adopt an autoinhibited configuration that is predicted to prevent Mcm2-7 loading; how the complex is activated and whether other ORC homologs can assume this state are not known. Using chemical cross-linking and mass spectrometry, biochemical assays, and electron microscopy (EM), we show that the autoinhibited state of Drosophila ORC is populated in solution, and that human ORC can also adopt this form...
June 13, 2018: Proceedings of the National Academy of Sciences of the United States of America
Sang Bum Kim, Lu Zhang, Jimok Yoon, Jeon Lee, Jaewon Min, Wenlin Li, Nick V Grishin, Young-Ah Moon, Woodring E Wright, Jerry W Shay
Adenomatous polyposis coli (APC) is a key molecule to maintain cellular homeostasis in colonic epithelium by regulating cell-cell adhesion, cell polarity, and cell migration through activating the APC-stimulated guanine nucleotide-exchange factor (Asef). The APC-activated Asef stimulates the small GTPase, which leads to decreased cell-cell adherence and cell polarity, and enhanced cell migration. In colorectal cancers, while truncated APC constitutively activates Asef and promotes cancer initiation and progression, regulation of Asef by full-length APC is still unclear...
June 4, 2018: Molecular and Cellular Biology
Jae Ho Lee, Sowmya Chandrasekar, SangYoon Chung, Yu-Hsien Hwang Fu, Demi Liu, Shimon Weiss, Shu-Ou Shan
Signal recognition particle (SRP) is a universally conserved targeting machine that mediates the targeted delivery of ∼30% of the proteome. The molecular mechanism by which eukaryotic SRP achieves efficient and selective protein targeting remains elusive. Here, we describe quantitative analyses of completely reconstituted human SRP (hSRP) and SRP receptor (SR). Enzymatic and fluorescence analyses showed that the ribosome, together with a functional signal sequence on the nascent polypeptide, are required to activate SRP for rapid recruitment of the SR, thereby delivering translating ribosomes to the endoplasmic reticulum...
May 30, 2018: Proceedings of the National Academy of Sciences of the United States of America
Cassandra R Harapas, Annemarie Steiner, Sophia Davidson, Seth L Masters
PURPOSE OF REVIEW: Autoinflammatory diseases are driven by abnormal innate immune activation. In the case of inflammasomopathies, these are all attributable to activation of an inflammasome complex, nucleated by an innate immune sensor such as NLRP3. This review will focus on recent advances that have helped to elucidate the role of three other sensors (NLRP1, NLRC4 and pyrin) which can also cause inflammasomopathies. RECENT FINDINGS: Mutations in pyrin (S242R or E244K) destroy an inhibitory 14-3-3 binding site and result in the newly characterised disease pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND)...
May 30, 2018: Current Rheumatology Reports
Seong-Ki Lee, Walter F Boron
Variant B of the electrogenic Na/HCO3 cotransporter (NBCe1-B) contributes to the vectorial transport of HCO3 - in epithelia (e.g., pancreatic ducts) and to the maintenance of intracellular pH in the central nervous systems (e.g., astrocytes). NBCe1-B has very low basal activity due to an autoinhibitory domain (AID), located, at least in part, in the unique portion (residues 1-85) of the cytosolic NH2 -terminus. Shcheynikov et al report that removing 23 amino acids (residues 40-62) stimulates NBCe1-B. Here, we test the hypothesis that a cationic cluster of 9 consecutive positively charged amino acids (residues 40-48) is a necessary part of the AID...
May 29, 2018: Journal of Physiology
Xingxian Luo, Taifeng Li, Ze Yu, Xuecai Xue, Haiyang Zhao, Na Li, Liping Ma, Changqing Yang, Lin Huanglin, Wangyu Feng
1. Imatinib is widely used for the treatment of hematologic malignancies. It is common that imatinib is clinically co-prescribed with azole antifungal agents since these patients are more prone to invasive antifungal infection. The present study was to investigate the effects of azole antifungal drugs, including ketoconazole, fluconazole, voriconazole, itraconazole and posaconazole on imatinib metabolism. 2. The main metabolites, 1-OH midazolam and N-desmethyl imatinib, were determined in the absence and in the presence of various levels of ketoconazole, fluconazole, voriconazole, itraconazole and posaconazole...
May 17, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Hiroaki Mizuno, Kotaro Tanaka, Sawako Yamashiro, Akihiro Narita, Naoki Watanabe
The complex interplay between actin regulatory proteins facilitates the formation of diverse cellular actin structures. Formin homology proteins (formins) play an essential role in the formation of actin stress fibers and yeast actin cables, to which the major actin depolymerizing factor cofilin barely associates. In vitro, F-actin decorated with cofilin exhibits a marked increase in the filament twist. On the other hand, a mammalian formin mDia1 rotates along the long-pitch actin helix during processive actin elongation (helical rotation)...
May 14, 2018: Proceedings of the National Academy of Sciences of the United States of America
Stuti Sharma, Rebecca A Oot, Stephan Wilkens
Vacuolar H+-ATPases (V-ATPases; V1Vo-ATPases) are rotary motor proton pumps that acidify intracellular compartments and in some tissues, the extracellular space. V-ATPase is regulated by reversible disassembly into autoinhibited V1-ATPase and Vo proton channel sectors. An important player in V-ATPase regulation is subunit H, which binds at the interface of V1 and Vo. H is required for MgATPase activity in holo V-ATPase, but also for stabilizing the MgADP inhibited state in membrane detached V1. However, how H fulfills these two functions is poorly understood...
May 12, 2018: Journal of Biological Chemistry
Alexander Hahn, Janet Vonck, Deryck J Mills, Thomas Meier, Werner Kühlbrandt
The chloroplast adenosine triphosphate (ATP) synthase uses the electrochemical proton gradient generated by photosynthesis to produce ATP, the energy currency of all cells. Protons conducted through the membrane-embedded Fo motor drive ATP synthesis in the F1 head by rotary catalysis. We determined the high-resolution structure of the complete cF1 Fo complex by cryo-electron microscopy, resolving side chains of all 26 protein subunits, the five nucleotides in the F1 head, and the proton pathway to and from the rotor ring...
May 11, 2018: Science
Jesper Torbøl Pedersen, Tamara Kanashova, Gunnar Dittmar, Michael Palmgren
The yeast plasma membrane H+ -ATPase Pma1p is a P-type ATPase that energizes the yeast plasma membrane. Pma1p exists in two activation states: an autoinhibited basal state and an activated state. Here we show that functional and stable Pma1p can be purified in native form and reconstituted in artificial liposomes without altering its activation state. Acetylated tubulin has previously been reported to maintain Pma1p in the basal state but, as this protein was absent from the purified preparations, it cannot be an essential component of the autoinhibitory mechanism...
May 2018: FEBS Open Bio
Angika Basant, Michael Glotzer
The active form of the small GTPase RhoA is necessary and sufficient for formation of a cytokinetic furrow in animal cells. Despite the conceptual simplicity of the process, the molecular mechanisms that control it are intricate and involve redundancy at multiple levels. Here, we discuss our current knowledge of the mechanisms underlying spatiotemporal regulation of RhoA during cytokinesis by upstream activators. The direct upstream activator, the RhoGEF Ect2, requires activation due to autoinhibition. Ect2 is primarily activated by the centralspindlin complex, which contains numerous domains that regulate its subcellular localization, oligomeric state, and Ect2 activation...
May 7, 2018: Current Biology: CB
Helen Walden, Katrin Rittinger
RBR ligases are an enigmatic class of E3 ubiquitin ligases that combine properties of RING and HECT-type E3s and undergo multilevel regulation through autoinhibition, post-translational modifications, multimerization and interaction with binding partners. Here, we summarize recent progress in RBR structures and function, which has uncovered commonalities in the mechanisms by which different family members transfer ubiquitin through a multistep process. However, these studies have also highlighted clear differences in the activity of different family members, suggesting that each RBR ligase has evolved specific properties to fit the biological process it regulates...
May 7, 2018: Nature Structural & Molecular Biology
Michael T Kelliher, Yang Yue, Ashley Ng, Daichi Kamiyama, Bo Huang, Kristen J Verhey, Jill Wildonger
Neuronal polarity relies on the selective localization of cargo to axons or dendrites. The molecular motor kinesin-1 moves cargo into axons but is also active in dendrites. This raises the question of how kinesin-1 activity is regulated to maintain the compartment-specific localization of cargo. Our in vivo structure-function analysis of endogenous Drosophila melanogaster kinesin-1 reveals a novel role for autoinhibition in enabling the dendrite-specific localization of Golgi outposts. Mutations that disrupt kinesin-1 autoinhibition result in the axonal mislocalization of Golgi outposts...
May 4, 2018: Journal of Cell Biology
Amy H Andreotti, Raji E Joseph, James M Conley, Janet Iwasa, Leslie J Berg
Signaling through the T cell antigen receptor (TCR) activates a series of tyrosine kinases. Directly associated with the TCR, the SRC family kinase LCK and the SYK family kinase ZAP-70 are essential for all downstream responses to TCR stimulation. In contrast, the TEC family kinase ITK is not an obligate component of the TCR cascade. Instead, ITK functions as a tuning dial, to translate variations in TCR signal strength into differential programs of gene expression. Recent insights into TEC kinase structure have provided a view into the molecular mechanisms that generate different states of kinase activation...
April 26, 2018: Annual Review of Immunology
Nathan Gamarra, Stephanie L Johnson, Michael J Trnka, Alma L Burlingame, Geeta Narlikar
ISWI family chromatin remodeling motors use sophisticated autoinhibition mechanisms to control nucleosome sliding. Yet how the different autoinhibitory domains are regulated is not well understood. Here we show that an acidic patch formed by histones H2A and H2B of the nucleosome relieves the autoinhibition imposed by the AutoN and the NegC regions of the human ISWI remodeler SNF2h. Further, by single molecule FRET we show that the acidic patch helps control the distance travelled per translocation event. We propose a model in which the acidic patch activates SNF2h by providing a landing pad for the NegC and AutoN auto-inhibitory domains...
April 17, 2018: ELife
Aaron A Cook, Wei Deng, Jinqi Ren, Renhao Li, John Sondek, Wolfgang Bergmeier
Platelets are recruited to sites of vascular injury, where they are activated and aggregate to form a hemostatic plug. This process requires the activation of the small GTPase Rap1B by its cognate guanine nucleotide exchange factor CalDAG-GEFI. Studies on platelet function suggest that CalDAG-GEFI activity is regulated by changes in cytosolic calcium, but the exact molecular mechanism is poorly understood. Here we show that purified CalDAG-GEFI is autoinhibited and directly regulated by calcium. Substitutions of putative calcium-binding residues within the canonical EF hands of CalDAG-GEFI diminish its capacity to activate Rap1B...
June 1, 2018: Journal of Biological Chemistry
Kai Wang, Junna He, Yang Zhao, Ting Wu, Xiaofeng Zhou, Yanglin Ding, Lingyao Kong, Xiaoji Wang, Yu Wang, Jigang Li, Chun-Peng Song, Baoshan Wang, Shuhua Yang, Jian-Kang Zhu, Zhizhong Gong
The reversible phosphorylation of proteins by kinases and phosphatases is an antagonistic process that modulates many cellular functions. Protein phosphatases are usually negatively regulated by inhibitor proteins. During abscisic acid (ABA) signaling, these inhibitor proteins comprise PYR1/PYL/RCAR ABA receptors, which inhibit the core negative regulators, the clade A type 2C protein phosphatases (PP2Cs). However, it is not known whether these PP2Cs are positively regulated by other proteins. Here, we identified an Arabidopsis thaliana ear1 ( enhancer of aba co-receptor1 ) mutant that exhibits pleiotropic ABA-hypersensitive phenotypes...
April 2018: Plant Cell
David R Paquette, Ryan W Tibble, Tristan S Daifuku, John D Gross
5' mediated cytoplasmic RNA decay is a conserved cellular process in eukaryotes. While the functions of the structured core domains in this pathway are well-studied, the role of abundant intrinsically disordered regions (IDRs) is lacking. Here we reconstitute the Dcp1:Dcp2 complex containing a portion of the disordered C-terminus and show its activity is autoinhibited by linear interaction motifs. Enhancers of decapping (Edc) 1 and 3 cooperate to activate decapping by different mechanisms: Edc3 alleviates autoinhibition by binding IDRs and destabilizing an inactive form of the enzyme, whereas Edc1 stabilizes the transition state for catalysis...
March 29, 2018: Nucleic Acids Research
Thomas Vogl, Athanasios Stratis, Viktor Wixler, Tom Völler, Sumita Thurainayagam, Selina K Jorch, Stefanie Zenker, Alena Dreiling, Deblina Chakraborty, Mareike Fröhling, Peter Paruzel, Corinna Wehmeyer, Sven Hermann, Olympia Papantonopoulou, Christiane Geyer, Karin Loser, Michael Schäfers, Stephan Ludwig, Monika Stoll, Tomas Leanderson, Joachim L Schultze, Simone König, Thomas Pap, Johannes Roth
Autoimmune diseases, such as psoriasis and arthritis, show a patchy distribution of inflammation despite systemic dysregulation of adaptive immunity. Thus, additional tissue-derived signals, such as danger-associated molecular patterns (DAMPs), are indispensable for manifestation of local inflammation. S100A8/S100A9 complexes are the most abundant DAMPs in many autoimmune diseases. However, regulatory mechanisms locally restricting DAMP activities are barely understood. We now unravel for the first time, to our knowledge, a mechanism of autoinhibition in mice and humans restricting S100-DAMP activity to local sites of inflammation...
May 1, 2018: Journal of Clinical Investigation
Thomas M Moon, Jessica L Sheehe, Praveena Nukareddy, Lydia W Nausch, Jessica Wohlfahrt, Dwight E Matthews, Donald K Blumenthal, Wolfgang R Dostmann
The type I cGMP-dependent protein kinases (PKG I) serve essential physiological functions, including smooth muscle relaxation, cardiac remodeling, and platelet aggregation. These enzymes form homodimers through their N-terminal dimerization domains, a feature implicated in regulating their cooperative activation. Previous investigations into the activation mechanisms of PKG I isoforms have been largely influenced by structures of the cAMP-dependent protein kinase (PKA). Here, we examined PKG Iα activation by cGMP and cAMP by engineering a monomeric form that lacks N-terminal residues 1-53 (Δ53)...
May 25, 2018: Journal of Biological Chemistry
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