Journal of Molecular Biology

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Editorial Board

Sun, 11/29/2015 - 23:48
Publication date: 4 December 2015
Source:Journal of Molecular Biology, Volume 427, Issue 24









Categories: Journal Articles

Contents List

Sun, 11/29/2015 - 23:48
Publication date: 4 December 2015
Source:Journal of Molecular Biology, Volume 427, Issue 24









Categories: Journal Articles

HSFs, Stress Sensors and Sculptors of Transcription Compartments and Epigenetic Landscapes

Sun, 11/29/2015 - 23:48
Publication date: 4 December 2015
Source:Journal of Molecular Biology, Volume 427, Issue 24

Author(s): Federico Miozzo, Délara Sabéran-Djoneidi, Valérie Mezger

Starting as a paradigm for stress responses, the study of the transcription factor (TF) family of heat shock factors (HSFs) has quickly and widely expanded these last decades, thanks to their fascinating and significant involvement in a variety of pathophysiological processes, including development, reproduction, neurodegeneration and carcinogenesis. HSFs, originally defined as classical TFs, strikingly appeared to play a central and often pioneering role in reshaping the epigenetic landscape. In this review, we describe how HSFs are able to sense the epigenetic environment, and we review recent data that support their role as sculptors of the chromatin landscape through their complex interplay with chromatin remodelers, histone-modifying enzymes and non-coding RNAs.
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Categories: Journal Articles

Solution NMR Studies of an Alternative Mode of Sin3 Engagement by the Sds3 Subunit in the Histone Deacetylase-Associated Sin3L/Rpd3L Corepressor Complex

Sun, 11/29/2015 - 23:48
Publication date: 4 December 2015
Source:Journal of Molecular Biology, Volume 427, Issue 24

Author(s): Michael David Clark, Yongbo Zhang, Ishwar Radhakrishnan

The Sds3 transcriptional corepressor facilitates the assembly of the 1- to 2-MDa histone deacetylase-associated Sin3L/Rpd3L complex by providing a crucial homodimerization activity. Sds3 engages the scaffolding protein Sin3A, via a bipartite motif within the Sin3 interaction domain (SID) comprising a helix and an extended segment. Here, we show that the SID samples two discrete, substantially populated conformations with lifetimes in the tens of milliseconds range. The two conformations differ via a translation of the main chain and the corresponding side chains in the 5- to 7-Å range. Given the close proximity of the SID to other functional motifs in Sds3 at the sequence level, the conformational exchange has the potential to regulate these activities.
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Categories: Journal Articles

Structure of Zeste–DNA Complex Reveals a New Modality of DNA Recognition by Homeodomain-Like Proteins

Sun, 11/29/2015 - 23:48
Publication date: 4 December 2015
Source:Journal of Molecular Biology, Volume 427, Issue 24

Author(s): Guan-Nan Gao, Mingzhu Wang, Na Yang, Ying Huang, Rui-Ming Xu

Drosophila Zeste is a DNA binding protein important for chromatin-targeted regulation of gene expression. It is best studied in the context of transvection—a mechanism of interallelic gene regulation involving paired chromosomes—and repression of the expression of white by Zeste mutants. Both of these functions depend on the DNA binding and self-association properties of Zeste, but the underlying structural basis remains unknown. Here we report the crystal structure of the DNA binding domain of Zeste in complex with a 19-bp DNA duplex containing the consensus recognition sequence motif. The structure reveals a helix–turn–helix Myb/homeodomain-like fold with the Zeste-specific insertion sequence forming a short helix and a long loop. Direct base contacts by the major groove binding helix principally account for the sequence-specific recognition, and backbone contacts via the Zeste-specific insertion are mainly responsible for the length requirement and the orientation of DNA. Our structural and biochemical characterizations of the DNA binding property of Zeste uncover an altered DNA binding modality of homeodomain-like proteins, and the structural information should facilitate the unraveling of the intricate mechanism of Zeste in regulation of gene expression.
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Categories: Journal Articles

The Bacterial Transcription Termination Factor Rho Coordinates Mg2+ Homeostasis with Translational Signals

Sun, 11/29/2015 - 23:48
Publication date: 4 December 2015
Source:Journal of Molecular Biology, Volume 427, Issue 24

Author(s): Michelle A. Kriner, Eduardo A. Groisman

The bacterial protein Rho triggers transcription termination at the ends of many operons and when transcription and translation become uncoupled. In addition to these genome wide activities, Rho implements regulation of specific genes by dictating whether RNA polymerase terminates transcription within the 5′ leader region or continues into the downstream coding region. Here, we report that the Mg2+ channel gene corA in Salmonella enterica serovar Typhimurium, which was previously thought to be constitutively expressed, is regulated by a Rho-dependent terminator located within its 5′ leader region. We demonstrate that the unusually long and highly conserved corA leader mRNA can adopt two mutually exclusive conformations that determine whether or not Rho interacts with a Rho utilization site on the nascent RNA and thereby prevents transcription of the corA coding region. The RNA conformation that promotes Rho-dependent termination is favored by efficient translation of corL, a short open reading frame located within the corA leader. Thus, corA transcription is inversely coupled to corL translation. This mechanism resembles those governing expression of Salmonella's other two Mg2+ transport genes, suggesting that Rho links Mg2+ uptake to translational signals.
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Categories: Journal Articles

Semi-Empirical Structure Determination of Escherichia coli Hsp33 and Identification of Dynamic Regulatory Elements for the Activation Process

Sun, 11/29/2015 - 23:48
Publication date: 4 December 2015
Source:Journal of Molecular Biology, Volume 427, Issue 24

Author(s): Yoo-Sup Lee, Jinhyuk Lee, Kyoung-Seok Ryu, Yuno Lee, Tai-Geun Jung, Jeong-Hwa Jang, Dae-Won Sim, Eun-Hee Kim, Min-Duk Seo, Keun Woo Lee, Hyung-Sik Won

The activation process of the redox-regulated chaperone heat shock protein 33 (Hsp33) is constituted by the oxidation-induced unfolding of the C-terminal zinc-binding domain and concomitant oligomerization of the N-terminal core domain. Herein, the semi-empirical solution structure of Escherichia coli Hsp33 in the reduced, inactive form was generated through conformational space annealing calculations, utilizing minimalistic NMR data and multiple homology restraints. The various conformations of oxidized Hsp33 and some mutant forms were also investigated in solution. Interestingly, a specific region concentrated around the interdomain linker stretch and its interacting counterparts, the N-terminal β-strand 1 and α-helix 1, hardly showed up as signals in the NMR measurements. The NMR spectra of an Hsp33 derivative with a six-residue deletion in the disordered N-terminus implied a plausible conformational exchange associated with the identified region, and the corresponding exchange rate appeared slower than that of the wild type. Subsequent mutations that destroyed the structure of the β1 or α1 elements resulted in the formation of a reduced but active monomer, without the unfolding of the zinc-binding domain. Collectively, structural insights into the inactive and active conformations, including wild-type and mutant proteins, suggest that the dynamic interactions of the N-terminal segments with their contacting counterpart, the interdomain linker stretch, in the reduced, inactive state are the structural determinants regulating the activation process of the post-translationally regulated chaperone, Hsp33.
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Categories: Journal Articles

Crystal Structure of the Human tRNA m1A58 Methyltransferase–tRNA3Lys Complex: Refolding of Substrate tRNA Allows Access to the Methylation Target

Sun, 11/29/2015 - 23:48
Publication date: 4 December 2015
Source:Journal of Molecular Biology, Volume 427, Issue 24

Author(s): Janet Finer-Moore, Nadine Czudnochowski, Joseph D. O'Connell, Amy Liya Wang, Robert M. Stroud

Human tRNA3 Lys is the primer for reverse transcription of HIV; the 3′ end is complementary to the primer-binding site on HIV RNA. The complementarity ends at the 18th base, A58, which in tRNA3 Lys is modified to remove Watson–Crick pairing. Motivated to test the role of the modification in terminating the primer-binding sequence and thus limiting run-on transcription, we asked how the modification of RNA could be accomplished. tRNA m1A58 methyltransferase (m1A58 MTase) methylates N1 of A58, which is buried in the TΨC-loop of tRNA, from cofactor S-adenosyl-l-methionine. This conserved tRNA modification is essential for stability of initiator tRNA in Saccharomyces cerevisiae. Reported here, three structures of human tRNA m1A58 MTase in complex with human tRNA3 Lys and the product S-adenosyl-l-homocysteine show a dimer of heterodimers in which each heterodimer comprises a catalytic chain, Trm61, and a homologous but noncatalytic chain, Trm6, repurposed as a tRNA-binding subunit that acts in trans; tRNAs bind across the dimer interface such that Trm6 from the opposing heterodimer brings A58 into the active site of Trm61. T-loop and D-loop are splayed apart showing how A58, normally buried in tRNA, becomes accessible for modification. This result has broad impact on our understanding of the mechanisms of modifying internal sites in folded tRNA. The structures serve as templates for design of inhibitors that could be used to test tRNA m1A58 MTase's impact on retroviral priming and transcription.
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Categories: Journal Articles

Hsp70 and Hsp90 of E. coli Directly Interact for Collaboration in Protein Remodeling

Sun, 11/29/2015 - 23:48
Publication date: 4 December 2015
Source:Journal of Molecular Biology, Volume 427, Issue 24

Author(s): Olivier Genest, Joel R. Hoskins, Andrea N. Kravats, Shannon M. Doyle, Sue Wickner

Hsp90 is a highly conserved molecular chaperone that remodels hundreds of client proteins, many involved in the progression of cancer and other diseases. It functions with the Hsp70 chaperone and numerous cochaperones. The bacterial Hsp90 functions with an Hsp70 chaperone, DnaK, but is independent of Hsp90 cochaperones. We explored the collaboration between Escherichia coli Hsp90 and DnaK and found that the two chaperones form a complex that is stabilized by client protein binding. A J-domain protein, CbpA, facilitates assembly of the Hsp90Ec–DnaK–client complex. We identified E. coli Hsp90 mutants defective in DnaK interaction in vivo and show that the purified mutant proteins are defective in physical and functional interaction with DnaK. Understanding how Hsp90 and Hsp70 collaborate in protein remodeling will provide the groundwork for the development of new therapeutic strategies targeting multiple chaperones and cochaperones.
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Categories: Journal Articles

Conformational Transitions that Enable Histidine Kinase Autophosphorylation and Receptor Array Integration

Sun, 11/29/2015 - 23:48
Publication date: 4 December 2015
Source:Journal of Molecular Biology, Volume 427, Issue 24

Author(s): Anna R. Greenswag, Alise Muok, Xiaoxiao Li, Brian R. Crane

During bacterial chemotaxis, transmembrane chemoreceptor arrays regulate autophosphorylation of the dimeric histidine kinase CheA. The five domains of CheA (P1–P5) each play a specific role in coupling receptor stimulation to CheA activity. Biochemical and X-ray scattering studies of thermostable CheA from Thermotoga maritima determine that the His-containing substrate domain (P1) is sequestered by interactions that depend upon P1 of the adjacent subunit. Non-hydrolyzable ATP analogs (but not ATP or ADP) release P1 from the protein core (domains P3P4P5) and increase its mobility. Detachment of both P1 domains or removal of one within a dimer increases net autophosphorylation substantially at physiological temperature (55°C). However, nearly all activity is lost without the dimerization domain (P3). The linker length between P1 and P3 dictates intersubunit (trans) versus intrasubunit (cis) autophosphorylation, with the trans reaction requiring a minimum length of 47 residues. A new crystal structure of the most active dimerization-plus-kinase unit (P3P4) reveals trans directing interactions between the tether connecting P3 to P2–P1 and the adjacent ATP-binding (P4) domain. The orientation of P4 relative to P3 in the P3P4 structure supports a planar CheA conformation that is required by membrane array models, and it suggests that the ATP lid of CheA may be poised to interact with receptors and coupling proteins. Collectively, these data suggest that the P1 domains are restrained in the off-state as a result of cross-subunit interactions. Perturbations at the nucleotide-binding pocket increase P1 mobility and access of the substrate His to P4-bound ATP.
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Categories: Journal Articles

Long-Range Energetic Changes Triggered by a Proline Switch in the Signal Adapter Protein c-CrkII

Sun, 11/29/2015 - 23:48
Publication date: 4 December 2015
Source:Journal of Molecular Biology, Volume 427, Issue 24

Author(s): Philipp A.M. Schmidpeter, Lena K. Ries, Tatjana Theer, Franz X. Schmid

The signal adapter protein c-CrkII from chicken but not from human uses isomerization at Pro238 in the SH3C domain to regulate the activity of the SH3N domain. The different behavior of human and chicken c-CrkII originates from only two differences in sequence, at positions 239 after Pro238 and 272 in the N-Src loop of SH3C. We analyzed the kinetics of substrate binding to SH3N and an assay for its coupling with Pro238 isomerization in SH3C to identify the molecular path from Pro238 to the substrate binding site of SH3N. The trans → cis isomerization at Pro238 and a relocation of Phe239 re-organize the energetics of a hydrophobic cluster in the N-Src loop of SH3C and re-shape this region to optimize its interactions with SH3N. Concomitantly, the backbone becomes strained at Met272. We suggest that, in human c-CrkII, movement at position 239 and strain at position 272 are not tolerated because the β-branched residues Ile239 and Val272 restrain the backbone mobility and thus destabilize the cis Pro238 form.
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Categories: Journal Articles

Structure of Full-Length Human PDGFRβ Bound to Its Activating Ligand PDGF-B as Determined by Negative-Stain Electron Microscopy

Sun, 11/29/2015 - 23:48
Publication date: 4 December 2015
Source:Journal of Molecular Biology, Volume 427, Issue 24

Author(s): Po-Han Chen, Vinzenz Unger, Xiaolin He

Members of the receptor tyrosine kinases (RTKs) regulate important cellular functions such as cell growth and migration, which are key steps in angiogenesis, in organ morphogenesis and in the unregulated states, cancer formation. One long-standing puzzle regarding RTKs centers on how the extracellular domain (ECD), which detects and binds to growth factors, is coupled with the intracellular domain kinase activation. While extensive structural works on the soluble portions of RTKs have provided critical insights into RTK structures and functions, lack of a full-length receptor structure has hindered a comprehensive overview of RTK activation. In this study, we successfully purified and determined a 27-Å-resolution structure of PDGFRβ [a full-length human platelet-derived growth factor receptor], in complex with its ligand PDGF-B. In the ligand-stimulated complex, two PDGFRβs assemble into a dimer via an extensive interface essentially running along the full-length of the receptor, suggesting that the membrane-proximal region, the transmembrane helix and the kinase domain of PDGFRβ are involved in dimerization. Major structural differences are seen between the full-length and soluble ECD structures, rationalizing previous experimental data on how membrane-proximal domains modulate receptor ligand-binding affinity and dimerization efficiency. Also, in contrast to the 2-fold symmetry of the ECD, the intracellular kinase domains adopt an asymmetric dimer arrangement, in agreement with prior observations for the closely related KIT receptor. In essence, the structure provides a first glimpse into how platelet-derived growth factor receptor ECD, upon ligand stimulation, is coupled to its intracellular domain kinase activation.
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Categories: Journal Articles

Structural and Functional Characterization of a Novel Family GH115 4-O-Methyl-α-Glucuronidase with Specificity for Decorated Arabinogalactans

Sun, 11/29/2015 - 23:48
Publication date: 4 December 2015
Source:Journal of Molecular Biology, Volume 427, Issue 24

Author(s): Friso Aalbers, Johan P. Turkenburg, Gideon J. Davies, Lubbert Dijkhuizen, Alicia Lammerts van Bueren

Glycoside hydrolases are clustered into families based on amino acid sequence similarities, and belonging to a particular family can infer biological activity of an enzyme. Family GH115 contains α-glucuronidases where several members have been shown to hydrolyze terminal α-1,2-linked glucuronic acid and 4-O-methylated glucuronic acid from the plant cell wall polysaccharide glucuronoxylan. Other GH115 enzymes show no activity on glucuronoxylan, and therefore, it has been proposed that family GH115 may be a poly-specific family. In this study, we reveal that a putative periplasmic GH115 from the human gut symbiont Bacteroides thetaiotaomicron, BtGH115A, hydrolyzes terminal 4-O-methyl-glucuronic acid residues from decorated arabinogalactan isolated from acacia tree. The three-dimensional structure of BtGH115A reveals that BtGH115A has the same domain architecture as the other structurally characterized member of this family, BoAgu115A; however the position of the C-terminal module is altered with respect to each individual enzyme. Phylogenetic analysis of GH115 amino sequences divides the family into distinct clades that may distinguish different substrate specificities. Finally, we show that BtGH115A α-glucuronidase activity is necessary for the sequential digestion of branched galactans from acacia gum by a galactan-β-1,3-galactosidase from family GH43; however, while B. thetaiotaomicron grows on larch wood arabinogalactan, the bacterium is not able to metabolize acacia gum arabinogalactan, suggesting that BtGH115A is involved in degradation of arabinogalactan fragments liberated by other microbial species in the gastrointestinal tract.
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Categories: Journal Articles

Patching broken DNA: Nucleosome dynamics and the repair of DNA breaks

Sun, 11/29/2015 - 23:48
Publication date: Available online 26 November 2015
Source:Journal of Molecular Biology

Author(s): Ozge Gursoy-Yuzugullu, Nealia House, Brendan D. Price

The ability of cells to detect and repair DNA double-strand breaks (DSBs) is dependent on reorganization of the surrounding chromatin structure by chromatin remodeling complexes. These complexes promote access to the site of DNA damage, facilitate processing of the damaged DNA and, importantly, are essential to repackage the repaired DNA. Here, we will review the chromatin remodeling steps which occur immediately after DSB production and which prepare the damaged chromatin template for processing by the DSB repair machinery. DSBs promote rapid accumulation of repressive complexes, including HP1, the NuRD complex, H2A.Z and histone methyltransferases at the DSB. This shift to a repressive chromatin organization may be important to inhibit local transcription and limit mobility of the break, and to maintain the DNA ends in close contact. Subsequently, the repressive chromatin is rapidly dismantled through a mechanism involving dynamic exchange of the histone variant H2A.Z. H2A.Z removal at DSBs alters the acidic patch on the nucleosome surface, promoting acetylation of the H4 tail (by the NuA4-Tip60 complex) and shifting the chromatin to a more open structure. Further, H2A.Z removal promotes chromatin ubiquitination and recruitment of additional DSB repair proteins to the break. Modulation of the nucleosome surface and nucleosome function during DSB repair therefore plays a vital role in processing of DNA breaks. Further, the nucleosome surface may function as a central hub during DSB repair, directing specific patterns of histone modification, recruiting DNA repair proteins and modulating chromatin packing during processing of the damaged DNA template.
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Categories: Journal Articles

Elements that Regulate the DNA Damage Response of Proteins Defective in Cockayne Syndrome

Sun, 11/29/2015 - 23:48
Publication date: Available online 23 November 2015
Source:Journal of Molecular Biology

Author(s): Teruaki Iyama, David M. Wilson

Cockayne syndrome (CS) is a premature aging disorder characterized by developmental defects, multisystem progressive degeneration, and sensitivity to ultraviolet light. CS is divided into two primary complementation groups, A and B, with the CSA and CSB proteins presumably functioning in DNA repair and transcription. Using laser microirradiation and confocal microscopy, we characterized the nature and regulation of the CS protein response to oxidative DNA damage, double-strand breaks (DSBs), angelicin monoadducts, and trioxsalen interstrand crosslinks (ICLs). Our data indicate that CSB recruitment is influenced by the type of DNA damage, and is most rapid and robust as follows: ICLs>DSBs>monoadducts>oxidative lesions. Transcription inhibition reduced accumulation of CSB at sites of monoadducts and ICLs, but did not affect recruitment to (although slightly affected retention at) oxidative damage. Inhibition of histone deacetylation altered the dynamics of CSB assembly, suggesting a role for chromatin status in the response to DNA damage, whereas the proteasome inhibitor MG132 had no effect. The C-terminus of CSB, and in particular its ubiquitin-binding domain, were critical to recruitment, while the N-terminus and a functional ATPase domain played a minor role at best in facilitating protein accumulation. Although the absence of CSA had no effect on CSB recruitment, CSA itself localized at sites of ICLs, DSBs and monoadducts, but not oxidative lesions. Our results reveal molecular components of the CS protein response and point to a major involvement of complex lesions in the pathology of CS.
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Categories: Journal Articles

Correct assembly of the bacteriophage T5 procapsid requires both the maturation protease and the portal complex

Sun, 11/29/2015 - 23:48
Publication date: Available online 23 November 2015
Source:Journal of Molecular Biology

Author(s): Alexis Huet, Robert L. Duda, Roger W. Hendrix, Pascale Boulanger, James F. Conway

The 90nm diameter capsid of coliphage T5 is organized with T=13 icosahedral geometry and encloses a dsDNA genome that measures 121 kbp. Its assembly follows a path similar to that of phage HK97 but yielding a larger structure that includes 775 subunits of the major head protein, 12 subunits of the portal protein and 120 subunits of the decoration protein. As for phage HK97, T5 encodes the scaffold function as an N-terminal extension (∆-domain) to the major head protein that is cleaved by the maturation protease after assembly of the initial prohead I form and prior to DNA packaging and capsid expansion. Although the major head protein alone is sufficient to assemble capsid-like particles, the yield is poor and includes many deformed structures. Here we explore the role of both the portal and protease in capsid assembly by generating constructs that include the major head protein and a combination of protease (wild type or an inactive mutant) and portal proteins, and overexpressing them in E. coli. Our results show that the inactive protease mutant acts to trigger assembly of the major head protein, probably through binding to the ∆-domain, while the portal protein regulates assembly into the correct T=13 geometry. A cryo-EM reconstruction of prohead I including inactivated protease reveals density projecting from the prohead interior surface toward its center that is compatible with the ∆-domain, and additional internal density that we assign as the inactivated protease. These results reveal complexity in T5 beyond that of the HK97 system.
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Categories: Journal Articles

Quantitative selection analysis of bacteriophage φCbK susceptibility in Caulobacter crescentus

Sun, 11/29/2015 - 23:48
Publication date: Available online 22 November 2015
Source:Journal of Molecular Biology

Author(s): Matthias Christen, Christian Beusch, Yvonne Bösch, Dario Cerletti, Carlos Eduardo Flores-Tinoco, Luca Del Medico, Flavia Tschan, Beat Christen

Classical molecular genetics uses stringent selective conditions to identify mutants with distinct phenotypic responses. Mutations giving rise to less pronounced phenotypes are often missed. However, to gain systems-level insights into complex genetic interaction networks requires genome-wide assignment of quantitative phenotypic traits. In this paper, we present a quantitative selection approach coupled with transposon sequencing (QS-TnSeq) to globally identify the cellular components that orchestrate susceptibility of the cell-cycle model bacterium Caulobacter crescentus towards bacteriophage φCbK infection. We found that 135 genes representing 3.30% of the Caulobacter genome exhibit significant accumulation of transposon insertions upon φCbK selection. More than 85% thereof consist of new factors not previously associated with phage φCbK susceptibility. Using hierarchical clustering of dose-dependent TnSeq datasets, we grouped these genes into functional modules that correlate with different stages of the φCbK infection process. We assign φCbK susceptibility to eight new genes that represent novel components of the pilus secretion machinery. Further, we demonstrate that from 86 motility genes, only seven genes encoding structural and regulatory components of the flagellar hook increase phage resistance when disrupted by transposons, suggesting a link between flagellar hook assembly and pili biogenesis. In addition, we observe high recovery of Tn5 insertions within regulatory sequences of the genes encoding the essential NADH:ubiquinone oxidoreductase complex indicating that intact proton motive force is crucial for effective phage propagation. In sum, QS-TnSeq is broadly applicable to perform quantitative and genome-wide systems-genetics analysis of complex phenotypic traits.
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Categories: Journal Articles

Editorial Board

Sun, 11/29/2015 - 23:48
Publication date: 20 November 2015
Source:Journal of Molecular Biology, Volume 427, Issue 23









Categories: Journal Articles

Contents List

Sun, 11/29/2015 - 23:48
Publication date: 20 November 2015
Source:Journal of Molecular Biology, Volume 427, Issue 23









Categories: Journal Articles

A Snapshot of the Extraordinary World of Social Microbiology

Sun, 11/29/2015 - 23:48
Publication date: 20 November 2015
Source:Journal of Molecular Biology, Volume 427, Issue 23

Author(s): Nicola R. Stanley-Wall, Sarah J. Coulthurst, Ian Barry Holland







Categories: Journal Articles