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Journal of Molecular Biology

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https://www.readbyqxmd.com/read/29791871/network-based-disease-module-discovery-by-a-novel-seed-connector-algorithm-with-pathobiological-implications
#1
Rui-Sheng Wang, Joseph Loscalzo
Understanding the genetic basis of complex diseases is challenging. Prior work shows that disease-related proteins do not typically function in isolation. Rather, they often interact with each other to form a network module that underlies dysfunctional mechanistic pathways. Identifying such disease modules will provide insights into a systems-level understanding of molecular mechanisms of diseases. Owing to the incompleteness of our knowledge of disease proteins and limited information on the biological mediators of pathobiological processes, the key proteins (seed proteins) for many diseases appear scattered over the human protein-protein interactome and form a few small branches, rather than coherent network modules...
May 20, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29787767/influence-of-gag-and-rre-sequences-on-hiv-1-rna-packaging-signal-structure-and-function
#2
Siarhei Kharytonchyk, Joshua D Brown, Krista Stilger, Saif Yasin, Aishwarya S Iyer, John Collins, Michael F Summers, Alice Telesnitsky
The packaging signal (Ψ) and Rev. responsive element (RRE), enable unspliced HIV-1 RNAs' export from the nucleus and packaging into virions. For some retroviruses, engrafting Ψ onto a heterologous RNA is sufficient to direct encapsidation. In contrast, HIV-1 RNA packaging requires 5' leader Ψ elements plus poorly defined additional features. We previously defined minimal 5' leader sequences competitive with intact Ψ for HIV-1 packaging, and here examined the potential roles of additional downstream elements...
May 19, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29787766/structure-and-functional-characterization-of-human-histidine-triad-nucleotide-binding-protein-1-mutations-associated-with-inherited-axonal-neuropathy-with-neuromyotonia
#3
Rachit M Shah, Kimberly M Maize, Harrison T West, Alexander M Strom, Barry C Finzel, Carston R Wagner
Inherited peripheral neuropathies are a group of neurodegenerative disorders that clinically affect 1 in 2500 individuals. Recently, genetic mutations in Human Histidine Nucleotide Binding Protein 1 (hHint1) have been strongly and most frequently associated with patients suffering from axonal neuropathy with neuromyotonia. However, the correlation between the impact of these mutations on the hHint1 structure, enzymatic activity and in vivo function has remained ambiguous. Here, we provide detailed biochemical characterization of a set of these hHint1 mutations...
May 19, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29787765/using-single-molecule-approaches-to-understand-the-molecular-mechanisms-of-heat-shock-protein-chaperone-function
#4
REVIEW
Caitlin L Johnston, Nicholas R Marzano, Antoine M van Oijen, Heath Ecroyd
The heat-shock proteins (Hsp) are a family of molecular chaperones, which collectively form a network that is critical for the maintenance of protein homeostasis. Traditional ensemble-based measurements have provided a wealth of knowledge on the function of individual Hsps and the Hsp network; however, such techniques are limited in their ability to resolve the heterogeneous, dynamic and transient interactions that molecular chaperones make with their client proteins. Single-molecule techniques have emerged as a powerful tool to study dynamic biological systems, as they enable rare and transient populations to be identified that would usually be masked in ensemble measurements...
May 19, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29787764/apobec3b-nuclear-localization-requires-two-distinct-n-terminal-domain-surfaces
#5
Daniel J Salamango, Jennifer L McCann, Özlem Demir, William L Brown, Rommie E Amaro, Reuben S Harris
The APOBEC3 family of cytosine deaminases catalyzes the conversion of cytosines-to-uracils in single-stranded DNA. Traditionally, these enzymes are associated with antiviral immunity and restriction of DNA-based pathogens. However, a role for these enzymes in tumor evolution and metastatic disease has also become evident. The primary APOBEC3 candidate in cancer mutagenesis is APOBEC3B (A3B) for three reasons: 1) A3B mRNA is upregulated in several different cancers, 2) A3B expression and mutational loads correlate with poor clinical outcomes, and 3) A3B is the only family member known to be constitutively nuclear...
May 19, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29782836/dancing-with-the-diva-hsp90-client-interactions
#6
REVIEW
Martina Radli, Stefan G D Rüdiger
The molecular chaperone Hsp90 is involved in the folding, maturation and degradation of a large number structurally and sequentially unrelated clients, often connected to serious diseases. Elucidating the principles of how Hsp90 recognises this large variety of substrates is essential for comprehending the mechanism of this chaperone machinery, as well as it is a prerequisite for the design of client specific drugs targeting Hsp90. Here, we discuss the recent progress in understanding the substrate recognition principles of Hsp90 and its implications for the role of Hsp90 in the lifecycle of (signalling) molecules...
May 18, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29782835/multi-pronged-interactions-underlie-inhibition-of-%C3%AE-synuclein-aggregation-by-%C3%AE-synuclein
#7
Jonathan K Williams, Xue Yang, Tamr B Atieh, Michael P Olson, Sagar D Khare, Jean Baum
The intrinsically disordered protein β-synuclein is known to inhibit the aggregation of its intrinsically disordered homolog, α-synuclein, which is implicated in Parkinson's disease. While β-synuclein itself does not form fibrils at the cytoplasmic pH7.4, alteration of pH and other environmental perturbations are known to induce its fibrilization. However, the sequence and structural determinants of β-synuclein inhibition and self-aggregation are not well understood. We have utilized a series of domain-swapped chimeras of α-synuclein and β-synuclein to probe the relative contributions of the N-terminal, C-terminal and the central Non-Amyloid-β Component (NAC) domains to the inhibition of α-synuclein aggregation...
May 18, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29782834/high-throughput-dissection-of-aav-host-interactions-the-fast-and-the-curious
#8
REVIEW
Anne-Kathrin Herrmann, Dirk Grimm
Over fifty years after its initial description, Adeno-associated virus (AAV) remains a most exciting but also most elusive study object in basic or applied virology. On the one hand, its simple structure not only facilitates investigations into virus biology, but combined with the availability of numerous natural AAV variants with distinct infection efficiency and specificity also makes AAV a preferred substrate for engineering of gene delivery vectors. On the other hand, it is striking to witness a recent flurry of reports that highlight and partially close persistent gaps in our understanding of AAV virus and vector biology...
May 18, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29782833/insights-into-stabilizing-forces-in-amyloid-fibrils-of-differing-sizes-from-polarizable-molecular-dynamics-simulations
#9
Darcy S Davidson, Anne M Brown, Justin A Lemkul
Pathological aggregation of amyloid-forming proteins is a hallmark of a number of human diseases, including Alzheimer's, type 2 diabetes, Parkinson's, and more. Despite having very different primary amino acid sequences, these amyloid proteins form similar supramolecular, fibril structures that are highly resilient to physical and chemical denaturation. To better understand the structural stability of disease-related amyloids and to gain a greater understanding of factors that stabilize functional amyloid assemblies, insights into tertiary and quaternary interactions are needed...
May 18, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29782832/nup159-weakens-gle1-binding-to-dbp5-but-does-not-accelerate-adp-release
#10
Emily V Wong, Shawn Gray, Wenxiang Cao, Rachel Montpetit, Ben Montpetit, Enrique M De La Cruz
Dbp5, DDX19 in humans, is an essential DEAD-box protein involved in mRNA export, which has also been linked to other cellular processes, including rRNA export and translation. Dbp5 ATPase activity is regulated by several factors, including RNA, the nucleoporin proteins Nup159 and Gle1, and the endogenous small molecule inositol hexakisphosphate (InsP6 ). To better understand how these factors modulate Dbp5 activity and how this modulation relates to in vivo RNA metabolism, a detailed characterization of the Dbp5 mechanochemical cycle in the presence of those regulators individually or together is necessary...
May 18, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29782831/mapping-cellular-polarity-networks-using-mass-spectrometry-based-strategies
#11
REVIEW
Avais M Daulat, Tania M Puvirajesinghe, Luc Camoin, Jean-Paul Borg
Cell polarity is a vital biological process involved in the building, maintenance and normal functioning of tissues in invertebrates and vertebrates. Unsurprisingly, molecular defects affecting polarity organization and functions have a strong impact on tissue homeostasis, embryonic development and adult life, and may directly or indirectly lead to diseases. Genetic studies have demonstrated the causative effect of several polarity genes in diseases, however much remains to be clarified before a comprehensive view of the molecular organization and regulation of the protein networks associated with polarity proteins is obtained...
May 18, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29778605/proteomic-and-biochemical-comparison-of-the-cellular-interaction-partners-of-human-vps33a-and-vps33b
#12
Morag R Hunter, Geoffrey G Hesketh, Tomasz H Benedyk, Anne-Claude Gingras, Stephen C Graham
Multi-subunit tethering complexes control membrane fusion events in eukaryotic cells. CORVET and HOPS are two such complexes, both containing the Sec1/Munc18 protein subunit VPS33A. Metazoans additionally possess VPS33B, which has considerable sequence similarity to VPS33A but does not integrate into CORVET or HOPS complexes and instead stably interacts with VIPAR. It has been recently suggested that VPS33B and VIPAR comprise two subunits of a novel multi-subunit tethering complex (named "CHEVI"), perhaps analogous in configuration to CORVET and HOPS...
May 17, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29778604/structural-basis-for-the-interaction-of-mutasome-assembly-factor-rev1-with-ubiquitin
#13
Gaofeng Cui, Maria Victoria Botuyan, Georges Mer
REV1 is an evolutionarily conserved Translesion synthesis (TLS) DNA polymerase and an assembly factor key for the recruitment of other TLS polymerases to DNA damage sites. REV1-mediated recognition of ubiquitin in the proliferative cell nuclear antigen (PCNA) is thought to be the trigger for TLS activation. Here we report the solution nuclear magnetic resonance (NMR) structure of a 108-residue fragment of human REV1 encompassing the two putative ubiquitin-binding motifs UBM1 and UBM2 in complex with ubiquitin...
May 17, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29778603/interrogating-the-dimerization-interface-of-the-prion-protein-via-site-specific-mutations-to-p-benzoyl-l-phenylalanine
#14
Sudheer Babu Sangeetham, Krisztina Huszár, Petra Bencsura, Antal Nyeste, Éva Hunyadi-Gulyás, Elfrieda Fodor, Ervin Welker
Transmissible spongiform encephalopathies are centered on the conformational transition of the prion protein from a mainly helical, monomeric structure to a β-sheet rich ordered aggregate. Experiments indicate that the main infectious and toxic species in this process are however shorter oligomers, formation of which from the monomers is yet enigmatic. Here, we created 25 variants of the mouse prion protein site-specifically containing one genetically-incorporated para-benzoyl-phenylalanine (pBpa), a cross-linkable non-natural amino acid, in order to interrogate the interface of a prion protein-dimer, which might lie on the pathway of oligomerization...
May 17, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29778602/structure-guided-combinatorial-engineering-facilitates-affinity-and-specificity-optimization-of-anti-cd81-antibodies
#15
Bryce Nelson, Jarrett Adams, Andreas Kuglstatter, Zhijian Li, Seth F Harris, Yang Liu, Sandya Bohini, Han Ma, Klaus Klumpp, Junjun Gao, Sachdev S Sidhu
Hepatitis C viral infection is the major cause of chronic hepatitis that affects as many as 71 million people worldwide. Rather than target the rapidly shifting viruses and their numerous serotypes, four independent antibodies were made to target the host antigen CD81 and were shown to block Hepatitis C viral entry. The single-chain variable fragment of each antibody was crystallized in complex with the CD81 large extracellular loop (LEL) in order to guide affinity maturation of two distinct antibodies by phage display...
May 17, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29777720/regulation-of-shigella-effector-kinase-ospg-through-modulation-of-its-dynamic-properties
#16
Andrey M Grishin, Kathryn R Barber, Ruo-Xu Gu, D Peter Tieleman, Gary S Shaw, Miroslaw Cygler
Gram-negative pathogens secrete effector proteins into human cells to modulate normal cellular processes and establish a bacterial replication niche. Shigella and pathogenic E. coli possess homologous effector kinases, OspG and NleH1/2, respectively. Upon translocation, OspG but not NleH binds to ubiquitin and a subset of E2~Ub conjugates, which was shown to activate its kinase activity. Here we show that OspG, having a minimal kinase fold, acquired a novel mechanism of regulation of its activity. Binding of the E2~Ub conjugate to OspG not only stimulates its kinase activity but also increases its optimal temperature for activity to match the human body temperature and stabilizes its labile C-terminal domain...
May 16, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29775635/enhanced-sampling-of-interdomain-motion-using-map-restrained-langevin-dynamics-and-nmr-application-to-pin1
#17
Jill J Bouchard, Junchao Xia, David A Case, Jeffrey W Peng
Many signaling proteins consist of globular domains connected by flexible linkers that allow for substantial domain motion. Because these domains often serve as complementary functional modules, the possibility of functionally important domain motions arises. To explore this possibility, we require knowledge of the ensemble of protein conformations sampled by interdomain motion. Measurements of NMR residual dipolar couplings (RDCs) of backbone NH bonds offer a per-residue characterization of interdomain dynamics, as the couplings are sensitive to domain orientation...
May 15, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29763584/equation-chapter-1-section-1sequence-to-conformation-relationships-of-disordered-regions-tethered-to-folded-domains-of-proteins
#18
Anuradha Mittal, Alex S Holehouse, Megan C Cohan, Rohit V Pappu
Intrinsically disordered proteins and regions (IDPs / IDRs) are characterized by well-defined sequence-to-conformation relationships (SCRs). These relationships refer to the sequence-specific preferences for average sizes, shapes, residue-specific secondary structure propensities, and amplitudes of multiscale conformational fluctuations. SCRs are discerned from the sequence-specific conformational ensembles of IDPs. A vast majority of IDPs are actually tethered to folded domains (FDs). This raises the question of whether or not SCRs inferred for IDPs are applicable to IDRs tethered to folded domains...
May 12, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29758263/page4-and-conformational-switching-insights-from-molecular-dynamics-simulations-and-implications-for-prostate-cancer
#19
Xingcheng Lin, Susmita Roy, Mohit Kumar Jolly, Federico Bocci, Nicholas P Schafer, Min-Yeh Tsai, Yihong Chen, Yanan He, Alexander Grishaev, Keith Weninger, John Orban, Prakash Kulkarni, Govindan Rangarajan, Herbert Levine, José N Onuchic
Prostate-Associated Gene 4 (PAGE4) is an intrinsically disordered protein (IDP) implicated in prostate cancer. The stress-response kinase Homeodomain-Interacting Protein Kinase 1 (HIPK1) phosphorylates two residues in PAGE4, serine 9 and threonine 51. Phosphorylation of these two residues facilitates the interaction of PAGE4 with Activator Protein-1 (AP-1) transcription factor complex to potentiate AP-1's activity. In contrast, hyperphosphorylation of PAGE4 by CDC-Like Kinase 2 (CLK2) attenuates this interaction with AP-1...
May 11, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29758262/s-adenosylhomocysteine-hydrolase-participates-in-dna-methylation-inheritance
#20
V K Chaithanya Ponnaluri, Pierre-Olivier Estève, Cristian I Ruse, Sriharsa Pradhan
DNA (cytosine-5) methyltransferase 1 (DNMT1) is essential for mammalian development and maintenance of DNA methylation following DNA replication in cells. The DNA methylation process generates S-adenosyl-L-homocysteine, a strong inhibitor of DNMT1. Here we report that S-adenosylhomocysteine hydrolase (SAHH/AHCY), the only mammalian enzyme capable of hydrolyzing S-adenosyl-L-homocysteine binds to DNMT1 during DNA replication. SAHH enhances DNMT1 activity in vitro, and its overexpression in mammalian cells led to hypermethylation of the genome, whereas its inhibition by adenosine periodate or siRNA mediated knock down resulted in hypomethylation of the genome...
May 11, 2018: Journal of Molecular Biology
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