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Lee C.-T.,National Cheng Kung University | Chen I.-T.,National Cheng Kung University | Chen I.-T.,University of Taipei | Yang Y.-T.,National Cheng Kung University | And 16 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

Acute hepatopancreatic necrosis disease (AHPND) is a severe, newly emergent penaeid shrimp disease caused by Vibrio parahaemolyticus that has already led to tremendous losses in the cultured shrimp industry. Until now, its disease-causing mechanism has remained unclear. Here we show that an AHPND-causing strain of V. parahaemolyticus contains a 70-kbp plasmid (pVA1) with a postsegregational killing system, and that the ability to cause disease is abolished by the natural absence or experimental deletion of the plasmid-encoded homologs of the Photorhabdus insect-related (Pir) toxins PirA and PirB. We determined the crystal structure of the V. parahaemolyticus PirA and PirB (PirAvp and PirBvp) proteins and found that the overall structural topology of PirAvp/PirBvp is very similar to that of the Bacillus Cry insecticidal toxin-like proteins, despite the low sequence identity (<10%). This structural similarity suggests that the putative PirABvp heterodimer might emulate the functional domains of the Cry protein, and in particular its poreforming activity. The gene organization of pVA1 further suggested that pirABvp may be lost or acquired by horizontal gene transfer via transposition or homologous recombination.


PubMed | National Quemoy University, National Tsing Hua University, Institute of Biological Chemistry and National Yang Ming University
Type: Journal Article | Journal: The Journal of biological chemistry | Year: 2016

We previously demonstrated that the epidermal growth factor receptor (EGFR) up-regulated miR-7 to promote tumor growth during lung cancer oncogenesis. Several lines of evidence have suggested that alterations in chromatin remodeling components contribute to cancer initiation and progression. In this study, we identified SMARCD1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily d, member 1) as a novel target gene of miR-7. miR-7 expression reduced SMARCD1 protein expression in lung cancer cell lines. We used luciferase reporters carrying wild type or mutated 3UTR of SMARCD1 and found that miR-7 blocked SMARCD1 expression by binding to two seed regions in the 3UTR of SMARCD1 and down-regulated SMARCD1 mRNA expression. Additionally, upon chemotherapy drug treatment, miR-7 down-regulated p53-dependent apoptosis-related gene BAX (BCL2-associated X protein) and p21 expression by interfering with the interaction between SMARCD1 and p53, thereby reducing caspase3 cleavage and the downstream apoptosis cascades. We found that although SMARCD1 sensitized lung cancer cells to chemotherapy drug-induced apoptosis, miR-7 enhanced the drug resistance potential of lung cancer cells against chemotherapy drugs. SMARCD1 was down-regulated in patients with non-small cell lung cancer and lung adenocarcinoma cell lines, and SMARCD1 and miR-7 expression levels were negatively correlated in clinical samples. Our investigation into the involvement of the EGFR-regulated microRNA pathway in the SWI/SNF chromatin remodeling complex suggests that EGFR-mediated miR-7 suppresses the coupling of the chromatin remodeling factor SMARCD1 with p53, resulting in increased chemo-resistance of lung cancer cells.


Chang H.-J.,Institute of Biological Chemistry | Chang H.-J.,National Taiwan University | Yang A.-S.,Academia Sinica, Taiwan
Methods in Molecular Biology | Year: 2014

Cystine-stabilized mini-proteins are important scaffolds in the combinatorial search of binders for molecular recognition. The structural determinants of a cystine-stabilized scaffold are the critical residues determining the formation of the native disulfide-bonding configuration, and thus should remain unchanged in the combinatorial libraries so as to allow a large portion of the library sequences to be compatible with the scaffold structure. A high-throughput molecular evolution procedure has been developed to select and screen for the polypeptide sequences folding into a specific cystine-stabilized structure. Patterns of sequence preference that emerge from the resultant sequence profiles provide structural determinant information, which facilitates the designs of combinatorial libraries for combinatorial approaches as in phage display. This methodology enables artificial cystine-stabilized proteins to be engineered with enhanced folding and binding properties. © 2014 Springer Science+Business Media, LLC .


PubMed | National Cheng Kung University, National Taiwan University, Taipei Medical University, Institute of Biological Chemistry and University of Arizona
Type: Comparative Study | Journal: Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

Acute hepatopancreatic necrosis disease (AHPND) is a severe, newly emergent penaeid shrimp disease caused by Vibrio parahaemolyticus that has already led to tremendous losses in the cultured shrimp industry. Until now, its disease-causing mechanism has remained unclear. Here we show that an AHPND-causing strain of V. parahaemolyticus contains a 70-kbp plasmid (pVA1) with a postsegregational killing system, and that the ability to cause disease is abolished by the natural absence or experimental deletion of the plasmid-encoded homologs of the Photorhabdus insect-related (Pir) toxins PirA and PirB. We determined the crystal structure of the V. parahaemolyticus PirA and PirB (PirA(vp) and PirB(vp)) proteins and found that the overall structural topology of PirA(vp)/PirB(vp) is very similar to that of the Bacillus Cry insecticidal toxin-like proteins, despite the low sequence identity (<10%). This structural similarity suggests that the putative PirAB(vp) heterodimer might emulate the functional domains of the Cry protein, and in particular its pore-forming activity. The gene organization of pVA1 further suggested that pirAB(vp) may be lost or acquired by horizontal gene transfer via transposition or homologous recombination.


Guh Y.-J.,Institute of Biological Chemistry | Guh Y.-J.,Academia Sinica, Taiwan | Yang C.-Y.,Academia Sinica, Taiwan | Liu S.-T.,National Taiwan Normal University | And 2 more authors.
Proceedings of the Royal Society B: Biological Sciences | Year: 2016

Oestrogen-related receptor α (ERRα) is an orphan nuclear receptor which is important for adaptive metabolic responses under conditions of increased energy demand, such as cold, exercise and fasting. Importantly, metabolism under these conditions is usually accompanied by elevated production of organic acids, which may threaten the body acid-base status. Although ERRα is known to help regulate ion transport by the renal epithelia, its role in the transport of acidbase equivalents remains unknown. Here, we tested the hypothesis that ERRα is involved in acidbase regulation mechanisms by using zebrafish as the model to examine the effects of ERRα on transepithelial H+ secretion. ERRα is abundantly expressed in H+-pump-rich cells (HR cells), a group of ionocytes responsible for H+ secretion in the skin of developing embryos, and its expression is stimulated by acidic (pH 4) environments. Knockdown of ERRα impairs both basal and low pH-induced H+ secretion in the yolk-sac skin, which is accompanied by decreased expression of H+secreting-related transporters. The effect of ERRα on H+ secretion is achieved through regulating both the total number of HR cells and the function of individual HR cells. These results demonstrate, for the first time, that ERRα is required for transepithelial H+ secretion for systemic acid-base homeostasis. © 2016 The Author(s) Published by the Royal Society. All rights reserved.


Liang S.-Y.,Institute of Biological Chemistry | Wu S.-W.,Academia Sinica, Taiwan | Pu T.-H.,Institute of Biological Chemistry | Chang F.-Y.,Academia Sinica, Taiwan | Khoo K.-H.,Academia Sinica, Taiwan
Bioinformatics | Year: 2014

Motivation: Despite many attempts for algorithm development in recent years, automated identification of intact glycopeptides from LC-MS2 spectral data is still a challenge in both sensitivity and precision. Results: We implemented a supervised machine learning algorithm, Random Forest, in an automated workflow to identify N-glycopeptides using spectral features derived from ion trap-based LC-MS2 data. The workflow streamlined high-confident N-glycopeptide spectral data and enabled adaptive model optimization with respect to different sampling strategies, training sample size and feature set. A critical evaluation of the features important for glycopeptide identification further facilitated effective feature selection for model improvement. Using split sample testing method from 577 high-confident N-glycopeptide spectral data, we demonstrated that an optimal true-positive rate, precision and false-positive rate of 73, 88 and 10%, respectively, can be attained for overall N-glycopeptide identification. © The Author 2014.


Li J.,Ohio State University | Poi M.J.,Ohio State University | Tsai M.-D.,Institute of Biological Chemistry
Biochemistry | Year: 2011

P16INK4A (also known as P16 and MTS1), a protein consisting exclusively of four ankyrin repeats, is recognized as a tumor suppressor mainly because of the prevalence of genetic inactivation of the p16INK4A (or CDKN2A) gene in virtually all types of human cancers. However, it has also been shown that an elevated level of expression (upregulation) of P16 is involved in cellular senescence, aging, and cancer progression, indicating that the regulation of P16 is critical for its function. Here, we discuss the regulatory mechanisms of P16 function at the DNA level, the transcription level, and the posttranscriptional level, as well as their implications for the structure-function relationship of P16 and for human cancers. © 2011 American Chemical Society.


Kamalov M.,Institute of Biological Chemistry | Kaur H.,University of Auckland | Brimble M.A.,University of Auckland
Chemistry - A European Journal | Year: 2016

Synthetic methods aimed at preparing peptides cross-linked by diaminodiacids remain an important chemical challenge. These cross-links are known to play a crucial role on the activity, structural stability, and folding of the host peptides and proteins. Recent developments in the syntheses of such systems have led to intriguing advances in the understanding of intermolecular side-chain cross-linking and the role that these structural motifs play in the biochemistry of proteins. Herein we provide an overview of the existing synthetic methodology that has been developed to effect protein cross-linking using diaminodiacids. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Kamalov M.,Institute of Biological Chemistry | Kaur H.,University of Auckland | Brimble M.A.,University of Auckland
Chemistry - A European Journal | Year: 2016

Synthetic methods aimed at preparing peptides cross-linked by diaminodiacids remain an important chemical challenge. These cross-links are known to play a crucial role on the activity, structural stability, and folding of the host peptides and proteins. Recent developments in the syntheses of such systems have led to intriguing advances in the understanding of intermolecular side-chain cross-linking and the role that these structural motifs play in the biochemistry of proteins. Herein we provide an overview of the existing synthetic methodology that has been developed to effect protein cross-linking using diaminodiacids. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Kirchhoff H.,Institute of Biological Chemistry
Plant signaling & behavior | Year: 2013

The thylakoid membrane system inside plants chloroplasts defines the structural framework for photosynthetic conversion of sunlight into metabolic energy forms (ATP, NADPH + H(+)). An architectural hallmark of these thylakoid membranes is the tight stacking of part of the membrane into cylindrical flat grana thylakoids, with a diameter of about 500 nm, that are interconnected by unstacked stroma lamellae forming a complex 3D network of alternating grana piles and stroma lamellae. The structural differentiation in the stacked and unstacked thylakoid regions is the basis for a pronounced spatial separation of multisubunit pigment-protein complexes that catalyze energy transformation. The main part of photosystem II (PSII) associated with light-harvesting complex II (LHCII) is concentrated in the grana thylakoids whereas PSI-LHCI and the ATPase complex are excluded from the stacked grana and accumulate in the unstacked thylakoid regions. The fifth protein complex, the cytochrome b 6f complex, is assumed to be homogenously distributed. It is important to recognize that this structural arrangement is not static but highly dynamic and responsive to environmental factors like light intensity and quality or temperature. Knowledge about the interplay between dynamic structural features of the intricate thylakoid architecture, and the functionality, regulation, repair and biogenesis of the photosynthetic machinery is essential for understanding the plasticity of energy conversion in plants living in a fluctuating multi-factorial environment.

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