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111.
112.
Wangsun Choi Bipul R. Acharya Grégoire Peyret Marc-Antoine Fardin René-Marc Mège Benoit Ladoux Alpha S. Yap Alan S. Fanning Mark Peifer 《The Journal of cell biology》2016,213(2):243-260
Morphogenesis requires dynamic coordination between cell–cell adhesion and the cytoskeleton to allow cells to change shape and move without losing tissue integrity. We used genetic tools and superresolution microscopy in a simple model epithelial cell line to define how the molecular architecture of cell–cell zonula adherens (ZA) is modified in response to elevated contractility, and how these cells maintain tissue integrity. We previously found that depleting zonula occludens 1 (ZO-1) family proteins in MDCK cells induces a highly organized contractile actomyosin array at the ZA. We find that ZO knockdown elevates contractility via a Shroom3/Rho-associated, coiled-coil containing protein kinase (ROCK) pathway. Our data suggest that each bicellular border is an independent contractile unit, with actin cables anchored end-on to cadherin complexes at tricellular junctions. Cells respond to elevated contractility by increasing junctional afadin. Although ZO/afadin knockdown did not prevent contractile array assembly, it dramatically altered cell shape and barrier function in response to elevated contractility. We propose that afadin acts as a robust protein scaffold that maintains ZA architecture at tricellular junctions. 相似文献
113.
HexaPEGylated hemoglobin (Hb), a non-hypertensive Hb, exhibits high O2 affinity, which makes it difficult for it to deliver the desired levels of oxygen to tissues. The PEGylation of very low O2 affinity Hbs is now contemplated as the strategy to generate PEGylated Hbs with intermediate levels of O2 affinity. Toward this goal, a doubly modified Hb with very low O2 affinity has been generated. The amino terminal of the beta-chain of HbA is modified by 2-hydroxy, 3-phospho propylation first to generate a low oxygen affinity Hb, HPPr-HbA. The oxygen affinity of this Hb is insensitive to DPG and IHP. Molecular modeling studies indicated potential interactions between the covalently linked phosphate group and Lys-82 of the trans beta-chain. To further modulate the oxygen affinity of Hb, the alpha alpha-fumaryl cross-bridge has been introduced into HPPr-HbA in the mid central cavity. The doubly modified HbA (alpha alpha-fumaryl-HPPr-HbA) exhibits an O2 affinity lower than that of either of the singly modified Hbs, with a partial additivity of the two modifications. The geminate recombination and the visible resonance Raman spectra of the photoproduct of alpha alpha-fumaryl-HPPr-HbA also reflect a degree of additive influence of each of these modifications. The two modifications induced a synergistic influence on the chemical reactivity of Cys-93(beta). It is suggested that the doubly modified Hb has accessed the low affinity T-state that is non-responsive to effectors. The doubly modified Hb is considered as a potential candidate for generating PEGylated Hbs with an O2 affinity comparable to that of erythrocytes for developing blood substitutes. 相似文献
114.
Shubhant Pandey Pranjal Mahanta Bryan W. Berger Rudresh Acharya 《The Journal of biological chemistry》2021,297(4)
Polysaccharide lyases (PLs) are a broad class of microbial enzymes that degrade anionic polysaccharides. Equally broad diversity in their polysaccharide substrates has attracted interest in biotechnological applications such as biomass conversion to value-added chemicals and microbial biofilm removal. Unlike other PLs, Smlt1473 present in the clinically relevant Stenotrophomonas maltophilia strain K279a demonstrates a wide range of pH-dependent substrate specificities toward multiple, diverse polysaccharides: hyaluronic acid (pH 5.0), poly-β-D-glucuronic (celluronic) acid (pH 7.0), poly-β-D-mannuronic acid, and poly-α-L-guluronate (pH 9.0). To decode the pH-driven multiple substrate specificities and selectivity in this single enzyme, we present the X-ray structures of Smlt1473 determined at multiple pH values in apo and mannuronate-bound states as well as the tetra-hyaluronate-docked structure. Our results indicate that structural flexibility in the binding site and N-terminal loop coupled with specific substrate stereochemistry facilitates distinct modes of entry for substrates having diverse charge densities and chemical structures. Our structural analyses of wild-type apo structures solved at different pH values (5.0–9.0) and pH-trapped (5.0 and 7.0) catalytically relevant wild-type mannuronate complexes (1) indicate that pH modulates the catalytic microenvironment for guiding structurally and chemically diverse polysaccharide substrates, (2) further establish that molecular-level fluctuation in the enzyme catalytic tunnel is preconfigured, and (3) suggest that pH modulates fluctuations resulting in optimal substrate binding and cleavage. Furthermore, our results provide key insight into how strategies to reengineer both flexible loop and regions distal to the active site could be developed to target new and diverse substrates in a wide range of applications. 相似文献
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The importance of sphingolipids in membrane biology was appreciated early in the twentieth century when several human inborn errors of metabolism were linked to defects in sphingolipid degradation. The past two decades have seen an explosion of information linking sphingolipids with cellular processes. Studies have unraveled mechanistic details of the sphingolipid metabolic pathways, and these findings are being exploited in the development of novel therapies, some now in clinical trials. Pioneering work in yeast has laid the foundation for identifying genes encoding the enzymes of the pathways. The advent of the era of genomics and bioinformatics has led to the identification of homologous genes in other species and the subsequent creation of animal knock-out lines for these genes. Discoveries from these efforts have re-kindled interest in the role of sphingolipids in membrane biology. This review highlights some of the recent advances in understanding sphingolipids' roles in membrane biology as determined from genetic models. 相似文献
117.
A marine, unicellular cyanobacterium, Synechococcus elongatus strain BDU/75042 was found to sequester uranium from aqueous systems at pH 7.8. The organism could remove 72% (53.5 mg U g?1 dry weight) of uranium from test solutions containing 100 μM uranyl carbonate within 1 h. The equilibrium data fitted well in the Langmuir isotherm thus suggesting a monolayer adsorption of uranium on the cyanobacterial biomass and predicted the maximum adsorption capacity of 124 mg U g?1 dry weight. Light and scanning electron microscopy coupled with energy dispersive X-ray fluorescence (EDXRF) spectroscopy confirmed the uranyl adsorption by this organism. Most of the bound uranium was found to be associated with the extracellular polysaccharides (EPS) suggesting its interaction with the surface active ligands. Fourier transform infrared (FT-IR) spectroscopy suggested the amide groups and the deprotonated carboxyl groups on the cyanobacterial cell surface were likely to be involved in uranyl adsorption. The cell bound uranium could be released by washing with ethylene diamine tetraacetic acid (EDTA) or 0.1 N HCl. The X-ray diffraction (XRD) analyses revealed the identity of uranium deposits associated with the cell biomass as uranyl carbonate hydrate. The study revealed the potential of this cyanobacterium for harvesting uranium from natural aquatic environments. 相似文献
118.
Alaguraj Veluchamy Sujitha Mary Vishal Acharya Preethi Mehta Taru Deva Sankaran Krishnaswamy 《Bioinformation》2009,4(2):80-83
The HNH Database is a collection and sequence-based classification of HNH domain proteins. The database contains about 1913 HNH
domain containing proteins, and is classified into 10 subsets based on the sequence pattern. Each of these subsets has unique signature
sequences. We have shown a correlation between the subset combination and their domain association and function. Functional divergence
of this domain may be due to the combination of these conserved patterns and the large variations in the non-conserved regions. HNHDb is
freely available at http://bicmku.in:8081/hnh. 相似文献
119.
120.
The CCN proteins are extracellular matrix associated proteins involved in critical cell activities and several aggressive forms of cancer. The proteins share a modular structure of four discrete domains and 38 conserved cysteine residues. The absence of any structural information of these proteins has resulted in a need for the ability to produce substantial amounts of pure CCN protein. Through bacterial expression and inclusion body based purification, pure recombinant CCN proteins have been produced for use in structural and biochemical experiments. 相似文献