scholarly journals Bioinformatics analysis of the structural and evolutionary characteristics for toll-like receptor 15

PeerJ ◽  
2016 ◽  
Vol 4 ◽  
pp. e2079 ◽  
Author(s):  
Jinlan Wang ◽  
Zheng Zhang ◽  
Fen Chang ◽  
Deling Yin
Keyword(s):  
Convex Surface ◽  
Purifying Selection ◽  
Structural Features ◽  
Protein Docking ◽  
Activation Process ◽  
Docking Analysis ◽  
Unique Role ◽  
Evolutionarily Conserved ◽  
Interaction Interface ◽  
Tir Domains

Toll-like receptors (TLRs) play important role in the innate immune system. TLR15 is reported to have a unique role in defense against pathogens, but its structural and evolution characterizations are still poorly understood. In this study, we identified 57 completed TLR15 genes from avian and reptilian genomes. TLR15 clustered into an individual clade and was closely related to family 1 on the phylogenetic tree. Unlike the TLRs in family 1 with the broken asparagine ladders in the middle, TLR15 ectodomain had an intact asparagine ladder that is critical to maintain the overall shape of ectodomain. The conservation analysis found that TLR15 ectodomain had a highly evolutionarily conserved region on the convex surface of LRR11 module, which is probably involved in TLR15 activation process. Furthermore, the protein–protein docking analysis indicated that TLR15 TIR domains have the potential to form homodimers, the predicted interaction interface of TIR dimer was formed mainly by residues from the BB-loops andαC-helixes. Although TLR15 mainly underwent purifying selection, we detected 27 sites under positive selection for TLR15, 24 of which are located on its ectodomain. Our observations suggest the structural features of TLR15 which may be relevant to its function, but which requires further experimental validation.

scholarly journals The structure of hookworm platelet inhibitor (HPI), a CAP superfamily member fromAncylostoma caninum

2015 ◽  
Vol 71 (6) ◽  
pp. 643-649 ◽  
Author(s):  
Dongying Ma ◽  
Ivo M. B. Francischetti ◽  
Jose M. C. Ribeiro ◽  
John F. Andersen
Keyword(s):  
Structural Features ◽  
Human Platelets ◽  
Sequence Motifs ◽  
Post Translational Modification ◽  
X Ray Diffraction ◽  
Platelet Inhibitor ◽  
Pathogenesis Related ◽  
Active Site Cleft ◽  
Interaction Interface ◽  
Protein Components

Secreted protein components of hookworm species include a number of representatives of the cysteine-rich/antigen 5/pathogenesis-related 1 (CAP) protein family known asAncylostoma-secreted proteins (ASPs). Some of these have been considered as candidate antigens for the development of vaccines against hookworms. The functions of most CAP superfamily members are poorly understood, but one form, the hookworm platelet inhibitor (HPI), has been isolated as a putative antagonist of the platelet integrins αIIbβ3and α2β1. Here, the crystal structure of HPI is described and its structural features are examined in relation to its possible function. The HPI structure is similar to those of other ASPs and shows incomplete conservation of the sequence motifs CAP1 and CAP2 that are considered to be diagnostic of CAP superfamily members. The asymmetric unit of the HPI crystal contains a dimer with an extensive interaction interface, but chromatographic measurements indicate that it is primarily monomeric in solution. In the dimeric structure, the putative active-site cleft areas from both monomers are united into a single negatively charged depression. A potential Lys-Gly-Asp disintegrin-like motif was identified in the sequence of HPI, but is not positioned at the apex of a tight turn, making it unlikely that it interacts with the integrin. Recombinant HPI produced inEscherichia coliwas found not to inhibit the adhesion of human platelets to collagen or fibrinogen, despite having a native structure as shown by X-ray diffraction. This result corroborates previous analyses of recombinant HPI and suggests that it might require post-translational modification or have a different biological function.

scholarly journals Genome-Wide Analysis of Multiple Organellar RNA Editing Factor Family in Poplar Reveals Evolution and Roles in Drought Stress

2019 ◽  
Vol 20 (6) ◽  
pp. 1425 ◽  
Author(s):  
Dongli Wang ◽  
Sen Meng ◽  
Wanlong Su ◽  
Yu Bao ◽  
Yingying Lu ◽  
...  
Keyword(s):  
Drought Stress ◽  
Rna Editing ◽  
Functional Divergence ◽  
Expression Patterns ◽  
Purifying Selection ◽  
Structural Features ◽  
Specific Expression ◽  
Poplar Genome ◽  
Physiological Processes ◽  
Genome Wide

Poplar (Populus) is one of the most important woody plants worldwide. Drought, a primary abiotic stress, seriously affects poplar growth and development. Multiple organellar RNA editing factor (MORF) genes—pivotal factors in the RNA editosome in Arabidopsis thaliana—are indispensable for the regulation of various physiological processes, including organelle C-to-U RNA editing and plasmid development, as well as in the response to stresses. Although the poplar genome sequence has been released, little is known about MORF genes in poplar, especially those involved in the response to drought stress at the genome-wide level. In this study, we identified nine MORF genes in the Populus genome. Based on the structural features of MORF proteins and the topology of the phylogenetic tree, the P. trichocarpa (Ptr) MORF family members were classified into six groups (Groups I–VI). A microsynteny analysis indicated that two (22.2%) PtrMORF genes were tandemly duplicated and seven genes (77.8%) were segmentally duplicated. Based on the dN/dS ratios, purifying selection likely played a major role in the evolution of this family and contributed to functional divergence among PtrMORF genes. Moreover, analysis of qRT-PCR data revealed that PtrMORFs exhibited tissue- and treatment-specific expression patterns. PtrMORF genes in all group were involved in the stress response. These results provide a solid foundation for further analyses of the functions and molecular evolution of MORF genes in poplar, and, in particular, for improving the drought resistance of poplar by genetics manipulation.

scholarly journals The ETS Domain Transcription Factor Elk-1 Contains a Novel Class of Repression Domain

2002 ◽  
Vol 22 (14) ◽  
pp. 5036-5046 ◽  
Author(s):  
Shen-Hsi Yang ◽  
Donna C. Bumpass ◽  
Neil D. Perkins ◽  
Andrew D. Sharrocks
Keyword(s):  
Transcription Factor ◽  
Map Kinases ◽  
Activation Process ◽  
Dependent Manner ◽  
New Class ◽  
Evolutionarily Conserved ◽  
Mitogen Activated Protein ◽  
Ets Domain ◽  
Context Dependent ◽  
Repression Domain

ABSTRACT The ETS domain transcription factor Elk-1 serves as an integration point for different mitogen-activated protein (MAP) kinase pathways. Phosphorylation of Elk-1 by MAP kinases triggers its activation. However, while the activation process is well understood, its downregulation-inactivation is less well characterized. The ETS DNA-binding domain plays a role in the downregulation of Elk-dependent promoter activity following mitogenic activation by recruiting the mSin3A-HDAC complex. Here we have identified a novel evolutionarily conserved repression domain in Elk-1, termed the R motif, which serves to reduce the basal transcriptional activity of Elk-1 and dampen its response to mitogenic signals. This domain is highly potent and portable and can repress transcription in trans. The R motif is related to the CRD1 repression domain in p300 and can functionally replace this domain and confer p21waf1/cip1 inducibility on p300. However, the R motif acts in a context-dependent manner and is not p21waf1/cip1 responsive in Elk-1. Thus, the Elk-1 R motif and the p300 CRD1 motif represent a new class of repression domains that are regulated in a context-dependent manner.

scholarly journals Unravelling novel synergies between organometallic and biological partners: a quantum mechanics/molecular mechanics study of an artificial metalloenzyme

2014 ◽  
Vol 11 (96) ◽  
pp. 20140090 ◽  
Author(s):  
Elisabeth Ortega-Carrasco ◽  
Agustí Lledós ◽  
Jean-Didier Maréchal
Keyword(s):  
Quantum Mechanics ◽  
Molecular Mechanics ◽  
Resting State ◽  
Structural Features ◽  
Activation Process ◽  
Biological Macromolecules ◽  
The Novel ◽  
Molecular Mechanics Calculations ◽  
Artificial Metalloenzymes ◽  
Artificial Metalloenzyme

In recent years, the design of artificial metalloenzymes obtained by the insertion of homogeneous catalysts into biological macromolecules has become a major field of research. These hybrids, and the corresponding X-ray structures of several of them, are offering opportunities to better understand the synergy between organometallic and biological subsystems. In this work, we investigate the resting state and activation process of a hybrid inspired by an oxidative haemoenzyme but presenting an unexpected reactivity and structural features. An extensive series of quantum mechanics/molecular mechanics calculations show that the resting state and the activation processes of the novel enzyme differ from naturally occurring haemoenzymes in terms of the electronic state of the metal, participation of the first coordination sphere of the metal and the dynamic process. This study presents novel insights into the sensitivity of the association between organometallic and biological partners and illustrates the molecular challenge that represents the design of efficient enzymes based on this strategy.

scholarly journals Self-association configures the NAD+-binding site of plant NLR TIR domains

2021 ◽  
Author(s):  
Hayden Burdett ◽  
Xiahao Hu ◽  
Maxwell X Rank ◽  
Natsumi Maruta ◽  
Bostjan Kobe
Keyword(s):  
Binding Site ◽  
Conformational Changes ◽  
Active Site ◽  
Binding Sites ◽  
Molecular Mechanisms ◽  
Structural Features ◽  
Active Conformation ◽  
Effector Triggered Immunity ◽  
Self Association ◽  
Tir Domains

TIR domains are signalling domains present in plant nucleotide-binding leucine-rich repeat receptors (NLRs), with key roles in plant innate immunity. They are required for the induction of a hypersensitive response (HR) in effector-triggered immunity, but the mechanism by which this occurs is not yet fully understood. It has been recently shown that the TIR domains from several plant NLRs possess NADase activity. The oligomeric structure of TIR-containing NLRs ROQ1 and RPP1 reveals how the TIR domains arrange into an active conformation, but low resolution around the NAD+ binding sites leaves questions unanswered about the molecular mechanisms linking self-association and NADase activity. In this study, a number of crystal structures of the TIR domain from the grapevine NLR RUN1 reveal how self-association and enzymatic activity may be linked. Structural features previously proposed to play roles involve the ″AE interface″ (mediated by helices A and E), the ″BB-loop″ (connecting β-strand B and helix B in the structure), and the ″BE interface″ (mediated by the BB-loop from one TIR and the ″DE surface″ of another). We demonstrate that self-association through the AE interface induces conformational changes in the NAD+-binding site, shifting the BB-loop away from the catalytic site and allowing NAD+ to access the active site. We propose that an intact ″DE surface″ is necessary for production of the signalling product (variant cyclic ADPR), as it constitutes part of the active site. Addition of NAD+ or NADP+ is not sufficient to induce self-association, suggesting that NAD+ binding occurs after TIR self-association. Our study identifies a mechanistic link between TIR self-association and NADase activity.

scholarly journals A Mechanism for the Rare Fluctuation that Powers Protein Conformational Change

2021 ◽  
Author(s):  
Shanshan Wu ◽  
Ao Ma
Keyword(s):  
Activation Barrier ◽  
Rare Event ◽  
Physical Nature ◽  
Structural Features ◽  
Isomerization Reaction ◽  
Activation Process ◽  
Space Condition ◽  
Reaction Coordinates ◽  
Gating Mechanism ◽  
Energy Activation

AbstractMost functional processes of biomolecules are rare events. Key to a rare event is the rare fluctuation that enables the energy activation process, which powers the system across the activation barrier. But the physical nature of this rare fluctuation and how it enables barrier crossing are unknown. With the help of a novel metric, the reaction capacity pC, that rigorously defines the beginning and parameterizes the progress of energy activation, the rare fluctuation was identified as a special phase-space condition that is necessary and sufficient for initiating systematic energy flow from the non-reaction coordinates into the reaction coordinates. The energy activation of a prototype biomolecular isomerization reaction is dominated by kinetic energy transferring into and accumulating in the reaction coordinates, administered by inertial forces alone. The two major reaction coordinates move in precise synergy, with one acting as a gating mechanism on the other. This mechanism is enabled by the structural features of biomolecules and may the cause of their unique functions that are not possible in small molecules.

scholarly journals Identification of Critical Residues in the Carboxy Terminus of the Dopamine Transporter Involved in the G Protein βγ-Induced Dopamine Efflux

2021 ◽  
Vol 12 ◽  
Author(s):  
José A. Pino ◽  
Gabriel Nuñez-Vivanco ◽  
Gabriela Hidalgo ◽  
Miguel Reyes Parada ◽  
Habibeh Khoshbouei ◽  
...  
Keyword(s):  
G Protein ◽  
Dopamine Transporter ◽  
Critical Role ◽  
Protein Docking ◽  
Physical Interaction ◽  
Amino Acid Residues ◽  
Carboxy Terminus ◽  
Docking Analysis ◽  
Critical Residues ◽  
Dopamine Efflux

The dopamine transporter (DAT) plays a crucial role in the regulation of brain dopamine (DA) homeostasis through the re-uptake of DA back into the presynaptic terminal. In addition to re-uptake, DAT is also able to release DA through a process referred to as DAT-mediated DA efflux. This is the mechanism by which potent and highly addictive psychostimulants, such as amphetamine (AMPH) and its analogues, increase extracellular DA levels in motivational and reward areas of the brain. Recently, we discovered that G protein βγ subunits (Gβγ) binds to the DAT, and that activation of Gβγ results in DAT-mediated efflux - a similar mechanism as AMPH. Previously, we have shown that Gβγ binds directly to a stretch of 15 residues within the intracellular carboxy terminus of DAT (residues 582–596). Additionally, a TAT peptide containing residues 582 to 596 of DAT was able to block the Gβγ-induced DA efflux through DAT. Here, we use a combination of computational biology, mutagenesis, biochemical, and functional assays to identify the amino acid residues within the 582–596 sequence of the DAT carboxy terminus involved in the DAT-Gβγ interaction and Gβγ-induced DA efflux. Our in-silico protein-protein docking analysis predicted the importance of F587 and R588 residues in a network of interactions with residues in Gβγ. In addition, we observed that mutating R588 to alanine residue resulted in a mutant DAT which exhibited attenuated DA efflux induced by Gβγ activation. We demonstrate that R588, and to a lesser extent F5837, located within the carboxy terminus of DAT play a critical role in the DAT-Gβγ physical interaction and promotion of DA efflux. These results identify a potential new pharmacological target for the treatment of neuropsychiatric conditions in which DAT functionality is implicated including ADHD and substance use disorder.

scholarly journals Selective constraint acting on TLR2 and TLR4 genes of Japanese Rana frogs

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e4842 ◽  
Author(s):  
Quintin Lau ◽  
Takeshi Igawa ◽  
Tiffany A. Kosch ◽  
Yoko Satta
Keyword(s):  
Innate Immunity ◽  
Batrachochytrium Dendrobatidis ◽  
Purifying Selection ◽  
Selective Constraint ◽  
Population Declines ◽  
Rana Japonica ◽  
Site Analysis ◽  
Evolutionarily Conserved ◽  
Frog Species ◽  
Molecular Patterns

Toll-like receptors (TLRs) are an important component of innate immunity, the first line of pathogen defence. One of the major roles of TLRs includes recognition of pathogen-associated molecular patterns. Amphibians are currently facing population declines and even extinction due to chytridiomycosis caused by the Batrachochytrium dendrobatidis (Bd) fungus. Evidence from other vertebrates shows that TLR2 and TLR4 are involved in innate immunity against various fungi. Such genes therefore may play a functional role in amphibian-chytridiomycosis dynamics. Frogs from East Asia appear to be tolerant to Bd, so we examined the genetic diversity that underlies TLR2 and TLR4 from three Japanese Ranidae frog species, Rana japonica, R. ornativentris and R. tagoi tagoi (n = 5 per species). We isolated 27 TLR2 and 20 TLR4 alleles and found that these genes are evolutionarily conserved, with overall evidence supporting purifying selection. In contrast, site-by-site analysis of selection identified several specific codon sites under positive selection, some of which were located in the variable leucine rich repeat domains. In addition, preliminary expression levels of TLR2 and TLR4 from transcriptome data showed overall low expression. Although it remains unclear whether infectious pathogens are a selective force acting on TLRs of Japanese frogs, our results support that certain sites in TLRs of these species may have experienced pathogen-mediated selection.

scholarly journals Non-neutral evolution of H3.3-encoding genes occurs without alterations in protein sequence

2018 ◽  
Author(s):  
Brejnev M. Muhire ◽  
Matthew A. Booker ◽  
Michael Y. Tolstorukov
Keyword(s):  
Codon Usage ◽  
Purifying Selection ◽  
Fine Tuning ◽  
Gene Arrangement ◽  
Neutral Evolution ◽  
Evolutionarily Conserved ◽  
Induced Genes ◽  
And Function ◽  
Evolutionary Paths ◽  
Encoding Genes

AbstractHistone H3.3 is a developmentally essential variant encoded by two independent genes in human (H3F3A and H3F3B). While this two-gene arrangement is evolutionarily conserved, its origins and function remain unknown. Phylogenetics, synteny and gene structure analyses of the H3.3 genes from 32 metazoan genomes indicate independent evolutionary paths for H3F3A and H3F3B. While H3F3B bears similarities with H3.3 genes in distant organisms and with canonical H3 genes, H3F3A is sarcopterygian-specific and evolves under strong purifying selection. Additionally, H3F3B codon-usage preferences resemble those of broadly expressed genes and ‘cell differentiation-induced’ genes, while codon-usage of H3F3A resembles that of ‘cell proliferation-induced’ genes. We infer that H3F3B is more similar to the ancestral H3.3 gene and likely evolutionarily adapted for broad expression pattern in diverse cellular programs, while H3F3A adapted for a subset of gene expression programs. Thus, the arrangement of two independent H3.3 genes facilitates fine-tuning of H3.3 expression across cellular programs.

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