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691.
Hironao Wakabayashi Amy E. Griffiths Philip J. Fay 《The Journal of biological chemistry》2010,285(33):25176-25184
Factor (F) VIII consists of a heavy chain (A1A2B domains) and light chain (A3C1C2 domains). The activated form of FVIII, FVIIIa, functions as a cofactor for FIXa in catalyzing the membrane-dependent activation of FX. Whereas the FVIII C2 domain is believed to anchor FVIIIa to the phospholipid surface, recent x-ray crystal structures of FVIII suggest that the C1 domain may also contribute to this function. We constructed a FVIII variant lacking the C2 domain (designated ΔC2) to characterize the contributions of the C1 domain to function. Binding affinity of the ΔC2 variant to phospholipid vesicles as measured by energy transfer was reduced ∼14-fold. However, the activity of ΔC2 as measured by FXa generation and one-stage clotting assays retained 76 and 36%, respectively, of the WT FVIII value. Modest reductions (∼4-fold) were observed in the functional affinity of ΔC2 FVIII for FIXa and rates of thrombin activation. On the other hand, deletion of C2 resulted in significant reductions in FVIIIa stability (∼3.6-fold). Thrombin generation assays showed peak thrombin and endogenous thrombin potential were reduced as much as ∼60-fold. These effects likely result from a combination of the intermolecular functional defects plus reduced protein stability. Together, these results indicate that FVIII domains other than C2, likely C1, make significant contributions to membrane-binding and membrane-dependent function. 相似文献
692.
YongChan Lee JongChan Park SoonWook Kweon MuHyeon Choe 《The Journal of biological chemistry》2010,285(8):5127-5131
Fab-PE38 used in this study is B3(Fab)-ext-PE38, and it is an antibody toxin that is made by fusing the Pseudomonas exotoxin to the Fab domain of B3 antibody. This antibody toxin selectively binds to cancer cells and kills the target cancer cells. B3(Fab)-ext-PE38 has a cysteine residue on the ext sequence, and (B3(Fab)-ext-PE38)2 is the disulfide-bridged dimer of the B3(Fab)-ext-PE38 monomer. (B3(Fab)-ext-PE38)2 has been found to have 11-fold higher cytotoxicity on the CRL-1739 cell line than monomeric B3(scFv)-PE38. We made a recombinant tandem repeat of the domain III of Streptococcal protein G that has Fab binding property up to seven repeats. Multiple monomers were found to form non-covalent complexes with this tandem repeat. Complexes were purified by size-exclusion chromatography, and we could enhance the production of the disulfide-bridged dimer by reduction and oxidation of the complexes. The tandem repeat makes close intermolecular interactions between monomers possible, and the use of it greatly enhances the yield of the disulfide-bridged dimer. 相似文献
693.
《Journal of structural biology》2021,213(4):107792
Half-turns are shown to be the main determinants of many experimental Alzheimer’s Aβ fibril structures. Fibril structures contain three half-turn types, βαRβ, βαLβ and βεβ which each result in a ∼90° bend in a β-strand. It is shown that only these half-turns enable cross-β stacking and thus the right-angle fold seen in fibrils is an intrinsic feature of cross-β. Encoding a strand as a conformational sequence in β, αR, αL and ε(βL), pairwise combination rules for consecutive half-turns are used to decode this sequence to give the backbone path. This reveals how structures would be dramatically affected by a deletion. Using a wild-type Aβ(42) fibril structure and the pairwise combination rules, the Osaka deletion is predicted to result in exposure of surfaces that are mutually shielding from the solvent. Molecular dynamics simulations on an 11-mer β-sheet of Alzheimer’s Aβ(40) of the Dutch (E22Q), Iowa (D23N), Arctic (E22G), and Osaka (E22Δ) mutants, show the crucial role glycine plays in the positioning of βαRβ half-turns. Their “in-phase” positions along the sequence in the wild-type, Dutch mutant and Iowa mutant means that the half-folds all fold to the same side creating the same closed structure. Their out-of-phase positions in Arctic and Osaka mutants creates a flatter structure in the former and an S-shape structure in the latter which, as predicted, exposes surfaces on the inside in the closed wild-type to the outside. This is consistent with the gain of interaction model and indicates how domain swapping might explain the Osaka mutant’s unique properties. 相似文献
694.
The intricacies of the 3D hierarchical organization of the genome have been approached by many creative modeling studies. The specific model/simulation technique combination defines and restricts the system and phenomena that can be investigated. We present the latest modeling developments and studies of the genome, involving models ranging from nucleosome systems and small polynucleosome arrays to chromatin fibers in the kb-range, chromosomes, and whole genomes, while emphasizing gene folding from first principles. Clever combinations allow the exploration of many interesting phenomena involved in gene regulation, such as nucleosome structure and dynamics, nucleosome-nucleosome stacking, polynucleosome array folding, protein regulation of chromatin architecture, mechanisms of gene folding, loop formation, compartmentalization, and structural transitions at the chromosome and genome levels. Gene-level modeling with full details on nucleosome positions, epigenetic factors, and protein binding, in particular, can in principle be scaled up to model chromosomes and cells to study fundamental biological regulation. 相似文献
695.
《Saudi Journal of Biological Sciences》2023,30(6):103676
The date palm, Phoenix dactylifera, is a vital crop in nations in the Middle East and North Africa. The date palm was thought to have outstanding traditional medicinal value because it was abundant in phytochemicals with diverse chemical structures. The date palm's ability to withstand harsh environments could be partly attributed to a class of proteins known as lectins, which are carbohydrate-binding proteins that can bind sugar moieties reversibly and without changing their chemical structures. After scanning the genome of P. dactylifera (GCF 009389715.1), this in silico study discovered 196 possible lectin homologs from 11 different families, some specific to plants. At the same time, others could also be found in other kingdoms of life. Their domain architectures and functional amino acid residues were investigated, and they yielded a 40% true-lectin with known conserved carbohydrate-binding residues. Further, their probable subcellular localization, physiochemical and phylogenetic analyses were also performed. Scanning all putative lectin homologs against the anticancer peptide (ACP) dataset found in the AntiCP2.0 webpage identified 26 genes with protein kinase receptors (Lec-KRs) belonging to 5 lectin families, which are reported to have at least one ACP motif. Our study offers the first account of Phoenix-lectins and their organization that can be used for further structural and functional analysis and investigating their potential as anticancer proteins. 相似文献
696.
Anastasia K. Zaytseva Artem M. Kiselev Alexander S. Boitsov Yulia V. Fomicheva Georgii S. Pavlov Boris S. Zhorov Anna A. Kostareva 《Biochemistry and Biophysics Reports》2022
Genetic variants in SCN5A gene were identified in patients with various arrhythmogenic conditions including Brugada syndrome. Despite significant progress of last decades in studying the molecular mechanism of arrhythmia-associated SCN5A mutations, the understanding of relationship between genetics, electrophysiological consequences and clinical phenotype is lacking. We have found a novel genetic variant Y739D in the SCN5A-encoded sodium channel Nav1.5 of a male patient with Brugada syndrome (BrS). The objective of the study was to characterize the biophysical properties of Nav1.5-Y739D and provide possible explanation of the phenotype observed in the patient. The WT and Y739D channels were heterologously expressed in the HEK-293T cells and the whole-cell sodium currents were recorded. Substitution Y739D reduced the sodium current density by 47 ± 2% at ?20 mV, positively shifted voltage-dependent activation, accelerated both fast and slow inactivation, and decelerated recovery from the slow inactivation. The Y739D loss-of-function phenotype likely causes the BrS manifestation. In the hNav1.5 homology models, which are based on the cryo-EM structure of rat Nav1.5 channel, Y739 in the extracellular loop IIS1-S2 forms H-bonds with K1381 and E1435 and pi-cation contacts with K1397 (all in loop IIIS5-P1). In contrast, Y739D accepts H-bonds from K1397 and Y1434. Substantially different contacts of Y739 and Y739D with loop IIIS5-P1 would differently transmit allosteric signals from VSD-II to the fast-inactivation gate at the N-end of helix IIIS5 and slow-inactivation gate at the C-end of helix IIIP1. This may underlie the atomic mechanism of the Y739D channel dysfunction. 相似文献
697.
MicroRNAs are prevalent regulators of gene expression, controlling most of the proteome in multicellular organisms. To generate the functional small RNAs, precise processing steps are required. In animals, microRNA biogenesis is initiated by Microprocessor that minimally consists of the Drosha enzyme and its partner, DGCR8. This first step is critical for selecting primary microRNAs, and many RNA-binding proteins and regulatory pathways target both the accuracy and efficiency of microRNA maturation. Structures of Drosha and DGCR8 in complex with primary microRNAs elucidate how RNA structural features rather than sequence provide the framework for substrate recognition. Comparing multiple states of Microprocessor and the closely related Dicer homologs shed light on the dynamic protein-RNA complex assembly and disassembly required to recognize RNAs with diverse sequences via common structural features. 相似文献
698.
Aurora M. Nedelcu 《Journal of molecular evolution》2009,68(3):256-268
Programmed cell death (PCD) represents a significant component of normal growth and development in multicellular organisms.
Recently, PCD-like processes have been reported in single-celled eukaryotes, implying that some components of the PCD machinery
existed early in eukaryotic evolution. This study provides a comparative analysis of PCD-related sequences across more than
50 unicellular genera from four eukaryotic supergroups: Unikonts, Excavata, Chromalveolata, and Plantae. A complex set of
PCD-related sequences that correspond to domains or proteins associated with all main functional classes—from ligands and
receptors to executors of PCD—was found in many unicellular lineages. Several PCD domains and proteins previously thought
to be restricted to animals or land plants are also present in unicellular species. Noteworthy, the yeast, Saccharomyces cerevisiae—used as an experimental model system for PCD research, has a rather reduced set of PCD-related sequences relative to other
unicellular species. The phylogenetic distribution of the PCD-related sequences identified in unicellular lineages suggests
that the genetic basis for the evolution of the complex PCD machinery present in extant multicellular lineages has been established
early in the evolution of eukaryotes. The shaping of the PCD machinery in multicellular lineages involved the duplication,
co-option, recruitment, and shuffling of domains already present in their unicellular ancestors.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
699.
Mohammad Tuhin ali Mohammed Monzur Morshed Md. Amran Gazi Md. Abu Musa Md Golam Kibria Md Jashim Uddin Md. Anik Ashfaq Khan Shihab Hasan 《Bioinformation》2014,10(8):533-538
Middle East Respiratory Syndrome Coronavirus (MERS-CoV) belongs to the coronaviridae family. In spite of several outbreaks in
the very recent years, no vaccine against this deadly virus is developed yet. In this study, the receptor binding domain (RBD) of
Spike (S) glycoprotein of MERS-CoV was analyzed through Computational Immunology approach to identify the antigenic
determinants (epitopes). In order to do so, the sequences of S glycoprotein that belong to different geographical regions were
aligned to observe the conservancy of MERS-CoV RBD. The immune parameters of this region were determined using different in
silico tools and Immune Epitope Database (IEDB). Molecular docking study was also employed to check the affinity of the potential
epitope towards the binding cleft of the specific HLA allele. The N-terminus RBD (S367-S606) of S glycoprotein was found to be
conserved among all the available strains of MERS-CoV. Based on the lower IC50 value, a total of eight potential T-cell epitopes and
19 major histocompatibility complex (MHC) class-I alleles were identified for this conserved region. A 9-mer epitope CYSSLILDY
displayed interactions with the maximum number of MHC class-I molecules and projected the highest peak in the B-cell
antigenicity plot which concludes that it could be a better choice for designing an epitope based peptide vaccine against MERSCoV
considering that it must undergo further in vitro and in vivo experiments. Moreover, in molecular docking study, this epitope
was found to have a significant binding affinity of -8.5 kcal/mol towards the binding cleft of the HLA-C*12:03 molecule. 相似文献
700.
Domain structure of flagellin 总被引:2,自引:0,他引:2
The chemotaxis of bacteria such as Salmonella and Escherichia coli involves smooth swimming punctuated by periods of tumbling. In smooth swimming the flagellar filaments are left-handed, in tumbling they are right-handed with a different wavelength. The filaments are constructed from a globular protein, flagellin, by a process of self-assembly. The existing models assume that the flagellin molecule is bistable and longitudinal rows of subunits take one of the two possible conformations. Such a model explains the observed different morphology of the flagellum. We have studied Salmonella and E. coli flagellins in polymeric and monomeric forms by scanning microcalorimetry and circular dichroism. We have inferred that a flagellin molecule consists of several domains, two of which are structured at physiological temperatures and are in the monomeric form, while the others acquire a regular form only in the process of polymerization. This phenomenon may be the basis of a process during which the flagellin molecule, fitting into the flagellum, acquires a conformation analogous to that of the neighbouring molecule in the longitudinal row. 相似文献