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Journal of Molecular Biology

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https://www.readbyqxmd.com/read/27916599/deciphering-communicating-and-engineering-the-crispr-pam
#1
REVIEW
Ryan T Leenay, Chase L Beisel
Clustered regularly interspaced short palindromic repeat (CRISPR) loci and their flanking CRISPR-associated (cas) genes make up RNA-guided, adaptive immune systems in prokaryotes whose effector proteins have become powerful tools for basic research and biotechnology. While the Cas effector proteins are remarkably diverse, they commonly rely on protospacer-adjacent motifs (PAMs) as the first step in target recognition. PAM sequences are known to vary considerably between systems and have proven to be difficult to predict, spurring the need for new tools to rapidly identify and communicate these sequences...
December 1, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27916598/pic-activation-through-functional-interplay-between-mediator-and-tfiih
#2
Sohail Malik, Henrik Molina, Zhu Xue
The multiprotein Mediator coactivator complex functions in large part by controlling formation and function of the promoter-bound preinitiation complex (PIC), which consists of RNA polymerase II (Pol II) and general transcription factors. However, precisely how Mediator impacts the PIC, especially post-recruitment, has remained unclear. Here, we have studied Mediator effects on basal transcription in an in vitro transcription system reconstituted from purified components. Our results reveal a close functional interplay between Mediator and TFIIH in the early stages of PIC development...
December 1, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27914894/scope-manual-curation-and-artifact-removal-in-the-structural-classification-of-proteins-extended-database
#3
John-Marc Chandonia, Naomi K Fox, Steven E Brenner
SCOPe (Structural Classification of Proteins - extended, http://scop.berkeley.edu) is a database of relationships between protein structures that extends the Structural Classification of Proteins (SCOP) database. SCOP is an expert-curated ordering of domains from the majority of proteins of known structure in a hierarchy according to structural and evolutionary relationships. SCOPe classifies the majority of protein structures released since SCOP development concluded in 2009, using a combination of manual curation and highly precise automated tools, aiming to have the same accuracy as fully hand-curated SCOP releases...
November 30, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27914893/near-atomic-resolution-structure-determination-of-a-cypovirus-capsid-and-polymerase-complex-using-cryo-em-at-200kv
#4
Xiaowu Li, Niyun Zhou, Wenyuan Chen, Bin Zhu, Xurong Wang, Bin Xu, Jiawei Wang, Hongrong Liu, Lingpeng Cheng
Single particle cryo-electron microscopy (cryo-EM) allows high-resolution structural determination of biological assemblies in a near-native environment. However, all high-resolution (better than 3.5Å) cryo-EM structures reported to date were obtained by using 300kV transmission electron microscopes (TEMs). We report here the structures of a cypovirus capsid of 750Å diameter at 3.3Å resolution and RNA-dependent RNA polymerase (RdRp) complexes within the capsid at 3.9Å resolution using a 200kV TEM. The newly resolved structure revealed conformational changes of two subdomains in the RdRp...
November 30, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27913116/multiple-conformations-of-gal3-protein-drive-the-galactose-induced-allosteric-activation-of-the-gal-genetic-switch-of-saccharomyces-cerevisiae
#5
Rajesh Kumar Kar, Hungyo Kharerin, Ranjith Padinhateeri, Paike Jayadeva Bhat
Gal3p is an allosteric monomeric protein which activates the GAL genetic switch of Saccharomyces cerevisiae in response to galactose. Expression of constitutive mutant of Gal3p or overexpression of wild-type Gal3p activates the GAL switch in the absence of galactose. These data suggest that Gal3p exists as an ensemble of active and inactive conformations. Structural data has indicated that Gal3p exists in open (inactive) and closed (active) conformations. However, mutant of Gal3p that predominantly exists in inactive conformation and yet capable of responding to galactose has not been isolated...
November 29, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27908641/free-energy-perturbation-calculation-of-relative-binding-free-energy-between-broadly-neutralizing-antibodies-and-the-gp120-glycoprotein-of-hiv-1
#6
Anthony J Clark, Tatyana Gindin, Baoshan Zhang, Lingle Wang, Robert Abel, Colleen S Murret, Fang Xu, Amy Bao, Nina J Lu, Tongqing Zhou, Peter D Kwong, Lawrence Shapiro, Barry Honig, Richard A Friesner
Direct calculation of relative binding affinities between antibodies and antigens is a long-sought goal. However, despite substantial efforts, no generally applicable computational method has been described. Here we describe a systematic free energy perturbation (FEP) protocol and calculate the binding affinities between the gp120 envelope glycoprotein of HIV-1 and three broadly neutralizing antibodies (bNAbs) of the VRC01 class. The protocol has been adapted from successful studies of small molecules to address the challenges associated with modeling protein-protein interactions...
November 28, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27899282/bindprofx-assessing-mutation-induced-binding-affinity-change-by-protein-interface-profiles-with-pseudo-counts
#7
Peng Xiong, Chengxin Zhang, Wei Zheng, Yang Zhang
Understanding how gene-level mutations affect the binding affinity of protein-protein interactions is a key issue of protein engineering. Due to the complexity of the problem, using physical force field to predict the mutation-induced binding free-energy change remains challenging. In this work, we present a renewed approach to calculate the impact of gene mutations on the binding affinity through the structure-based profiling of protein-protein interfaces, where the binding free-energy change (ΔΔG) is counted as the logarithm of relative probability of mutant amino acids over wild-type ones in the interface alignment matrix; three pseudo counts are introduced to alleviate the limit of the current interface library...
November 26, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27894815/the-histone-variant-h3-3-in-transcriptional-regulation-and-human-disease
#8
REVIEW
Leilei Shi, Hong Wen, Xiaobing Shi
Histone proteins wrap around DNA to form nucleosomes, which further compact into higher order structure of chromatin. In addition to the canonical histones, there are also variant histones that often have pivotal roles in regulating chromatin dynamics and the accessibility of the underlying DNA. H3.3 is the most common non-centromeric variant of histone H3 that differs from the canonical H3 by just 4-5 amino acids. Here we discuss the current knowledge of H3.3 in transcriptional regulation and the recent discoveries and molecular mechanisms of H3...
November 25, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27890784/identifying-residues-that-determine-scf-molecular-level-interactions-through-a-combination-of-experimental-and-in-silico-analyses
#9
Eitan Rabinovich, Michael Heyne, Anna Bakhman, Mickey Kosloff, Julia M Shifman, Niv Papo
The stem cell factor (SCF)/c-Kit receptor tyrosine kinase complex - with its significant roles in hematopoiesis and angiogenesis - is an attractive target for rational drug design. There is thus a need to map, in detail, the SCF/c-Kit interaction sites and the mechanisms that modulate this interaction. While most residues in the direct SCF/c-Kit binding interface can be identified from the existing crystal structure of the complex, other residues that affect binding through protein unfolding, intermolecular interactions, or allosteric or long-distance electrostatic effects cannot be directly inferred...
November 24, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27890783/the-proline-glycine-rich-region-of-the-biofilm-adhesion-protein-aap-forms-an-extended-stalk-that-resists-compaction
#10
Alexander E Yarawsky, Lance R English, Steven T Whitten, Andrew B Herr
Staphylococcus epidermidis is one of the primary bacterial species responsible for healthcare-associated infections. The most significant virulence factor for S. epidermidis is its ability to form a biofilm, which renders the bacteria highly resistant to host immune responses and antibiotic action. Intercellular adhesion within the biofilm is mediated by the accumulation-associated protein (Aap), a cell wall-anchored protein that self-assembles in a zinc-dependent manner. The C-terminal portion of Aap contains a proline/glycine-rich, 135 amino acid-long region that has not yet been characterized...
November 24, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27890782/bromodomain-histone-readers-and-cancer
#11
REVIEW
Abhinav K Jain, Michelle C Barton
Lysine acetylation of histone proteins is a fundamental post-translational modification that regulates chromatin structure and plays an important role in gene transcription. Aberrant levels of histone lysine acetylation are associated with the development of several diseases. Acetyl-lysine modifications create docking sites for bromodomains, which are structurally conserved modules present in transcription-associated proteins that are termed "reader" proteins. Bromodomain-containing reader proteins are part of multi-protein complexes that regulate transcription programs, often associated with profound phenotypic changes...
November 24, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27889474/the-von-willebrand-factor-a1-collagen-iii-interaction-is-independent-of-conformation-and-type-2-von-willebrand-disease-phenotype
#12
Venkata R Machha, Alexander Tischer, Laurie Moon-Tasson, Matthew Auton
The blood von Willebrand factor (VWF) mediates platelet adhesion to injured vessels by sequestering platelets from blood flow and depositing them to collagen and other exposed subendothelial matrix proteins. This process of capturing platelets to facilitate formation of platelet plugs occurs through transient interactions with platelet glycoprotein Ibα via the VWF A1 domain which also binds collagen. Using a conformationally diverse collection of natively folded and mutation-induced misfolded von Willebrand disease (VWD) variants, we test a recently proposed affinity up-regulation hypothesis which states that collagen binding changes the conformation of the A1 domain to a high-affinity GPIbα binding competent state...
November 24, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27887869/a-highly-diverse-and-functional-na%C3%A3-ve-ubiquitin-variant-library-for-generation-of-intracellular-affinity-reagents
#13
Isabel Leung, Nick Jarvik, Sachdev S Sidhu
We report the design, construction, and validation of a highly diverse phage-displayed naïve ubiquitin variant (Ubv) library. We first conducted a mutation tolerance scan of 27 residues and confirmed that 24 of these could be substituted by chemically diverse amino acids without compromising the display of Ubvs on phage. Subsequently, we constructed a library containing 6.8×10(10) unique members, in which these 24 positions were diversified with a degenerate codon that encodes for 6 aa that are prevalent in protein interaction sites...
November 22, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27887868/reassessing-apobec3g-inhibition-by-hiv-1-vif-derived-peptides
#14
Christopher M Richards, Ming Li, Angela L Perkins, Anurag Rathore, Daniel A Harki, Reuben S Harris
The human APOBEC3G (A3G) enzyme restricts HIV-1 in the absence of the viral accessory protein viral infectivity factor (Vif) by deaminating viral cDNA cytosines to uracils. These uracil lesions base-pair with adenines during the completion of reverse transcription and result in A3G signature G-to-A mutations in the viral genome. Vif protects HIV-1 from A3G-mediated restriction by forming an E3-ubiquitin ligase complex to polyubiquitinate A3G and trigger its degradation. Prior studies indicated that Vif may also directly block the enzymatic activity of A3G and, provocatively, that Vif-derived peptides, Vif 25-39 and Vif 105-119, are similarly inhibitory...
November 22, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27884606/bag3-is-a-modular-scaffolding-protein-that-physically-links-heat-shock-protein-70-hsp70-to-the-small-heat-shock-proteins
#15
Jennifer N Rauch, Eric Tse, Rebecca Freilich, Sue-Ann Mok, Leah N Makley, Daniel R Southworth, Jason E Gestwicki
Small heat shock proteins (sHsps) are a family of ATP-independent molecular chaperones that are important for binding and stabilizing unfolded proteins. In this task, the sHsps have been proposed to coordinate with ATP-dependent chaperones, including heat shock protein 70 (Hsp70). However, it is not yet clear how these two important components of the chaperone network are linked. We report that the Hsp70 co-chaperone, BAG3, is a modular, scaffolding factor to bring together sHsps and Hsp70s. Using domain deletions and point mutations, we found that BAG3 uses both of its IPV motifs to interact with sHsps, including Hsp27 (HspB1), αB-crystallin (HspB5), Hsp22 (HspB8), and Hsp20 (HspB6)...
November 21, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27884605/arsenic-induced-activation-of-the-homeodomain-interacting-protein-kinase-2-hipk2-to-camp-response-element-binding-protein-creb-axis
#16
Kazunori Hashimoto, Yoshiaki Tsuji
CREB (cAMP-response element binding protein) plays key transcriptional roles in cell metabolism, proliferation, and survival. Ser133 phosphorylation by protein kinase A (PKA) is a well-characterized CREB activation mechanism. HIPK2 (homeodomain interacting protein kinase 2), a nuclear serine/threonine kinase, activates CREB through Ser271 phosphorylation; however, the regulatory mechanism remains uncharacterized. Transfection of CREB in HEK293 cells together with the kinase demonstrated that HIPK2 phosphorylated CREB at Ser271 but not Ser133, likewise PKA phosphorylated CREB at Ser133 but not Ser271, suggesting two distinct CREB regulatory mechanisms by HIPK2 and PKA...
November 21, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27876548/the-effects-of-replication-stress-on-s-phase-histone-management-and-epigenetic-memory
#17
REVIEW
Saša Šviković, Julian E Sale
When a cell divides it must not only accurately duplicate its genome but must also recapitulate its programme of gene expression. A significant body of evidence suggests that an important fraction of the information specifying the transcriptional programme of vertebrate cells is carried epigenetically by post-translational modifications of histone proteins. For such a system to operate, propagation of key histone marks must be coupled to replication such that they remain correctly associated with the underlying DNA sequence, despite the huge disruption to chromatin structure generated by unwinding the parental DNA strands...
November 19, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27871933/a-molecular-prospective-for-hira-complex-assembly-and-h3-3-specific-histone-chaperone-function
#18
REVIEW
M Daniel Ricketts, Ronen Marmorstein
Incorporation of variant histone sequences, in addition to post-translational modification of histones, serves to modulate the chromatin environment. Different histone chaperone proteins mediate the storage and chromatin deposition of variant histones. Although the two non-centromeric histone H3 variants, H3.1 and H3.3, differ by only 5 aa, replacement of histone H3.1 with H3.3 can modulate the transcription for highly expressed and developmentally required genes, lead to the formation of repressive heterochromatin, or aid in DNA and chromatin repair...
November 19, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27871932/s100a10-regulates-ulk1-localization-to-er-mitochondria-contact-sites-in-ifn-%C3%AE-triggered-autophagy
#19
Ying-Da Chen, Yi-Ting Fang, Chih-Peng Chang, Chiou-Feng Lin, Li-Jin Hsu, Shang-Rung Wu, Yen-Chi Chiu, Robert Anderson, Yee-Shin Lin
During the process of autophagy, the autophagy-related proteins are translocated to autophagosome formation sites. Here, we demonstrate that S100A10 is required for ULK1 localization to autophagosome formation sites. Silencing of S100A10 reduces IFN-γ-induced autophagosome formation. We also determined the role of annexin A2 (ANXA2), a binding partner of S100A10, which has been reported to promote phagophore assembly. Silencing of ANXA2 reduced S100A10 expression. However, overexpression of S100A10 in ANXA2-silenced cells was still able to enhance autophagosome formation, suggesting that ANXA2 regulates IFN-γ-induced autophagy through S100A10...
November 19, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27865781/imaging-transcriptional-regulation-of-eukaryotic-mrna-genes-advances-and-outlook
#20
REVIEW
Jie Yao
Regulation of eukaryotic transcription in vivo occurs at distinct stages. Previous research has identified many active or repressive transcription factors (TFs) and core transcription components and studied their functions in vitro and in vivo. Nonetheless, how individual TFs act in concert to regulate mRNA gene expression in a single cell remains poorly understood. Direct observation of TF assembly and disassembly and various biochemical reactions during transcription of a single-copy gene in vivo is the ideal approach to study this problem...
November 16, 2016: Journal of Molecular Biology
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