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Journal of Molecular Biology

Javier Santos-Moreno, Alexandra East, Ingrid Guilvout, Nathalie Nadeau, Peter J Bond, Guy Tran Van Nhieu, Olivera Francetic
Bacterial type 2 secretion systems (T2SS), type 4 pili (T4P) and archaeal flagella assemble fibres from initially membrane-embedded pseudopilin and pilin subunits. Fibre subunits are made as precursors with positively charged N-terminal anchors, whose cleavage via the prepilin peptidase, essential for pilin membrane extraction and assembly, is followed by N-methylation of the mature (pseudo)pilin N-terminus. The conserved Glu residue at position 5 (E5) of mature (pseudo)pilins is essential for assembly. Unlike T4 pilins, where E5 residue substitutions also abolish N-methylation, the E5A variant of T2SS pseudopilin PulG remains N-methylated, but is affected in interaction with the T2SS component PulM...
April 17, 2017: Journal of Molecular Biology
Katharina F Witting, Monique P C Mulder, Huib Ovaa
Post-translational protein modification by ubiquitin (Ub) and ubiquitin-like modifiers (Ubl) is orchestrated by the sequential action of ubiquitin activating, conjugating, and ligating enzymes to regulate a vast array of fundamental biological processes. Unsurprisingly, the dysregulation of the intricate interplay between ubiquitination and deubiquitination gives rise to numerous pathologies, most notably cancer and neurodegenerative diseases. While activity-based probes (ABPs) and assay reagents have been extensively developed and applied for deubiquitinating enzymes (DUBs), similar tools for the ubiquitin cascade have only recently emerged...
April 11, 2017: Journal of Molecular Biology
Rosanne L L Hill, Jiri Vlach, Laura K Parker, Gail E Christie, Jamil S Saad, Terje Dokland
Staphylococcus aureus is an opportunistic human pathogen able to transfer virulence genes to other cells through the mobilization of S. aureus pathogenicity islands (SaPIs). SaPIs are derepressed and packaged into phage-like transducing particles by helper phages like 80α or φNM1. Phages 80α and φNM1 encode structurally distinct dUTPases, Dut80α (type 1) and DutNM1 (type 2). Both dUTPases can interact with the SaPIbov1 Stl master repressor, leading to derepression and mobilization. That two structurally distinct dUTPases bind the same repressor led us to speculate that dUTPase activity may be important to the derepression process...
April 8, 2017: Journal of Molecular Biology
Xuetian Yue, Yuhan Zhao, Yang Xu, Min Zheng, Zhaohui Feng, Wenwei Hu
Tumor suppressor p53 plays a central role in tumor suppression. p53 is the most frequently mutated gene in human cancer, and over half of human cancers contain p53 mutations. Majority of p53 mutations in cancer are missense mutations, leading to the expression of full-length mutant p53 protein. While the critical role of wild type p53 in tumor suppression has been firmly established, mounting evidence has demonstrated that many tumor-associated mutant p53 proteins not only lose tumor suppressive function of wild type p53, but also gain new activities to promote tumorigenesis independently of wild type p53, termed gain-of-function...
April 5, 2017: Journal of Molecular Biology
Jiří Koubek, Yi-Che Chang, Sunny Yao-Chen Yang, Joseph Jen-Tse Huang
Protein biogenesis is poorly understood due to the ribosome which perturbs measurement attempted on the ribosome-bound nascent chain (RNC). Investigating nascent chain dynamics may provide invaluable insight into the co-translational processes such as structure formation or interaction with a chaperone, e.g. the bacterial Trigger Factor (TF). In this study, we aim to establish a platform for studying nascent chain dynamics by exploring the local environment near the fluorescent dye on site-specifically labeled RNCs with time-resolved fluorescence anisotropy...
April 3, 2017: Journal of Molecular Biology
Alexandre Faille, Sabine Gavalda, Nawel Slama, Christian Lherbet, Laurent Maveyraud, Valérie Guillet, Françoise Laval, Annaïk Quémard, Lionel Mourey, Jean-Denis Pedelacq
Dehydration reactions play a crucial role for de novo biosynthesis of fatty acids and a wide range of pharmacologically active polyketide natural products with strong emphasis in human medicine. The type I polyketide synthase PpsC from Mycobacterium tuberculosis catalyzes key biosynthetic steps of lipid virulence factors phthiocerol dimycocerosates (DIM) and phenolic glycolipids (PGL). Given the insolubility of the natural C28-C30 fatty acyl substrate of the PpsC DH domain, we investigated its structure-function relationships in the presence of shorter surrogate substrates...
April 1, 2017: Journal of Molecular Biology
Sumana Venkat, Caroline Gregory, Jourdan Sturges, Qinglei Gan, Chenguang Fan
Protein acetylation plays important roles in many biological processes. Malate dehydrogenase (MDH), a key enzyme in the tricarboxylic acid cycle, has been identified to be acetylated in bacteria by proteomic studies, but no further characterization has been reported. One challenge for studying protein acetylation is to get purely acetylated proteins at specific positions. Here, we applied the genetic code expansion strategy to site-specifically incorporate N(ε)-acetyllysine into MDH. The acetylation of lysine residues in MDH could enhance its enzyme activity...
March 31, 2017: Journal of Molecular Biology
Raul Vallejos Baier, Joao Picao-Osorio, Claudio R Alonso
Alternative polyadenylation (APA) is a widespread gene regulatory mechanism that generates mRNAs with different 3'-ends allowing them to interact with different sets of RNA regulators such as microRNAs and RNA-binding proteins. Recent studies have shown that during development neural tissues produce mRNAs with particularly long 3'UTRs suggesting that such extensions might be important to neural development and function. Despite this, the mechanisms underlying neural APA are not well understood. Here we investigate this problem within the Drosophila nervous system focusing on the roles played by general cleavage/poly(A) (CPA) factors...
March 30, 2017: Journal of Molecular Biology
Aline Marnef, Sarah Cohen, Gaëlle Legube
For decades, it has been speculated that specific loci on eukaryotic chromosomes are inherently susceptible to breakage. The advent of high throughput genomic technologies has now paved the way to their identification. A wealth of data suggest that transcriptionally active loci are particularly fragile and that a specific DNA Damage Response is activated and dedicated to their repair. Here we review current understanding of the crosstalk between transcription and DSB repair, from the reasons underlying the intrinsic fragility of genes to the mechanisms that restore the integrity of damaged transcription units...
March 28, 2017: Journal of Molecular Biology
Soumya Daturpalli, Robert A Knieß, Chung-Tien Lee, Matthias P Mayer
Hsp90 chaperones the late folding steps of many protein kinases, transcription factors and a diverse set of other protein clients not related in sequence and structure. Hsp90's interaction with clients appears to be coupled to a series of conformational changes. How these conformational changes contribute to its chaperone activity is currently unclear. Using crosslinking, hydrogen exchange mass spectrometry, and fluorescence experiments we demonstrate here that the N-terminal domain of Hsp90 rotates by approximately 180° as compared to the crystal structure of yeast Hsp90 in complex with Sba1 and AMPPNP...
March 28, 2017: Journal of Molecular Biology
Tianyang Liu, Anbang Dai, Yong Cao, Rui Zhang, Meng-Qiu Dong, Hong-Wei Wang
WASP homolog associated with actin, membranes, and microtubules (WHAMM) is a vertebrate protein functioning in membrane tubulation for intracellular membrane trafficking and specific organelle formation. Composed of multiple domains, WHAMM can bind to membrane and microtubule (MT) and promote actin polymerization nucleation. Previous work revealed that WHAMM's activity to promote actin nucleation is repressed upon binding to MTs. Here, we discovered that WHAMM interacts with αβ-tubulin through a small peptide motif within its MT-binding domain...
March 25, 2017: Journal of Molecular Biology
Tim Kükenshöner, Nadine Eliane Schmit, Emilie Bouda, Fern Sha, Florence Pojer, Akiko Koide, Markus Seeliger, Shohei Koide, Oliver Hantschel
The binding of Src-homology 2 (SH2) domains to phosphotyrosine (pY) sites is critical for the autoinhibition and substrate recognition of the eight Src family kinases (SFKs). The high sequence conservation of the 120 human SH2 domains poses a significant challenge to selectively perturb the interactions of even the SFK SH2 family against the rest of the SH2 domains. We have developed synthetic binding proteins, termed monobodies, for six of the SFK SH2 domains with nanomolar affinity. Most of these monobodies competed with pY ligand binding and showed strong selectivity for either the SrcA (Yes, Src, Fyn, Fgr) or SrcB subgroup (Lck, Lyn, Blk, Hck)...
March 25, 2017: Journal of Molecular Biology
Christina M Lucato, Christopher C Lupton, Michelle L Halls, Andrew M Ellisdon
The misfolding of proteins to form amyloid is a key pathological feature of several progressive, and currently incurable, diseases. A mechanistic understanding of the pathway from soluble, native protein to insoluble amyloid is crucial for therapeutic design and recent efforts have helped to elucidate the key molecular events that trigger protein misfolding. Generally, either global or local structural perturbations occur early in amyloidogenesis to expose aggregation-prone regions of the protein that can then self-associate to form toxic oligomers...
March 22, 2017: Journal of Molecular Biology
Masaaki Nakashima, Shinya Tsuzuki, Hiroaki Awazu, Akiko Hamano, Ayaka Okada, Hirotaka Ode, Masami Maejima, Atsuko Hachiya, Yoshiyuki Yokomaku, Nobuhisa Watanabe, Hirofumi Akari, Yasumasa Iwatani
The APOBEC3 (A3) family of cellular cytidine deaminases comprises seven members (A, B, C, D, F, G, and H) that potently inhibit retroviral replication. Human immunodeficiency virus type 1 (HIV-1) Vif is a small pleiotropic protein that specifically inactivates these enzymes, targeting them for ubiquitin-mediated proteasomal degradation. A3 Vif-interaction sites are presumed to fall into three distinct types: A3C/D/F, A3G, and A3H. To date, two types of A3G and A3C/D/F sites have been well characterized, whereas the A3H Vif-binding site remains poorly defined...
March 21, 2017: Journal of Molecular Biology
Robert Lindner, Elisabeth Hartmann, Miroslaw Tarnawski, Andreas Winkler, Daniel Frey, Jochen Reinstein, Anton Meinhart, Ilme Schlichting
Light-regulated enzymes enable organisms to quickly respond to changing light conditions. We characterize a photoactivatable adenylyl cyclase from Beggiatoa sp. (bPAC) that translates a blue light signal into production of the second messenger cyclic AMP. bPAC contains a BLUF photoreceptor domain that senses blue light using a flavin chromophore, linked to an adenylyl cyclase (AC) domain. We present a dark state crystal structure of bPAC that closely resembles the recently published structure of the homologous OaPAC from Oscillatoria acuminata...
March 20, 2017: Journal of Molecular Biology
Jane S Richardson, Lizbeth L Videau, Christopher J Williams, David C Richardson
Vicinal disulfides between sequence-adjacent cysteine residues are very rare and rather startling structural features which play a variety of functional roles. Typically discussed as an isolated curiosity, they have never received a general treatment covering both cis and trans forms. Enabled by the growing database of high-resolution structures, required deposition of diffraction data, and improved methods for discriminating reliable from dubious cases, we identify and describe distinct protein families with reliably genuine examples of cis or trans vicinal disulfides and discuss their conformations, conservation, and functions...
March 20, 2017: Journal of Molecular Biology
Rob van der Kant, Anne R Karow-Zwick, Joost Van Durme, Michaela Blech, Rodrigo Gallardo, Daniel Seeliger, Kerstin Aßfalg, Pieter Baatsen, Griet Compernolle, Ann Gils, Joey M Studts, Patrick Schulz, Patrick Garidel, Joost Schymkowitz, Frederic Rousseau
Protein aggregation remains a major area of focus in the production of monoclonal antibodies. Improving the intrinsic properties of antibodies can improve manufacturability, attrition rates, safety, formulation, titers, immunogenicity, and solubility. Here, we explore the potential of predicting and reducing the aggregation propensity of monoclonal antibodies, based on the identification of aggregation-prone regions and their contribution to the thermodynamic stability of the protein. Although aggregation-prone regions are thought to occur in the antigen binding region to drive hydrophobic binding with antigen, we were able to rationally design variants that display a marked decrease in aggregation propensity while retaining antigen binding through the introduction of artificial aggregation gatekeeper residues...
March 18, 2017: Journal of Molecular Biology
Aranda R Duan, Erin M Jonasson, Emily O Alberico, Chunlei Li, Jared P Scripture, Rachel A Miller, Mark S Alber, Holly V Goodson
Tau is a multifaceted neuronal protein that stabilizes microtubules (MTs), but the mechanism of this activity remains poorly understood. Questions include whether Tau binds MTs laterally or longitudinally, and whether Tau's binding affinity depends on the nucleotide state of tubulin. We observed that Tau binds tightly to Dolastatin-10 tubulin rings and promotes the formation of Dolastatin-10 ring stacks, implying that Tau can crosslink MT protofilaments laterally. In addition, we found that Tau prefers GDP-like tubulin conformations, which implies that Tau binding to the MT surface is biased away from the dynamic GTP-rich MT tip...
March 17, 2017: Journal of Molecular Biology
Qinming Chen, Renliang Yang, Nikolay Korolev, Chuan Fa Liu, Lars Nordenskiöld
Chromatin folding and dynamics are critically dependent on nucleosome - nucleosome interactions with important contributions from inter-nucleosome binding of the histone H4 N-terminal tail K16-R23 domain to the surface of the H2A/H2B dimer. The H4 Lys16 plays a pivotal role in this regard. Using in vitro reconstituted 12-mer nucleosome arrays we have investigated the mechanism of the H4 N-terminal tail in maintaining nucleosome-nucleosome stacking and mediating intra- and inter-array chromatin compaction, with emphasis on the role of K16 and the positive charge region, R17-R23...
March 16, 2017: Journal of Molecular Biology
Ananda Ayyappan Jaguva Vasudevan, Henning Hofmann, Dieter Willbold, Dieter Häussinger, Bernd W Koenig, Carsten Münk
The retroviral restriction factors of the APOBEC3 (A3) cytidine deaminase family catalyze the deamination of cytidines in single-stranded viral DNA. APOBEC3C (A3C) is a strong antiviral factor against viral infectivity factor (vif)-deficient simian immunodeficiency virus Δvif, which is, however, a weak inhibitor against human immunodeficiency virus (HIV)-1 for reasons unknown. The precise link between the antiretroviral effect of A3C and its catalytic activity is incompletely understood. Here, we show that the S61P mutation in human A3C (A3C...
March 16, 2017: Journal of Molecular Biology
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