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Dudev T.,Academia Sinica, Taiwan | Lim C.,Academia Sinica, Taiwan | Lim C.,National Tsing Hua University
Chemical Reviews | Year: 2014

Metal cations are the simplest, but most versatile, cofactors in protein biochemistry with a plethora of distinctive properties. Intracellular and extracellular fluids contain a mixture of metal cations present in different concentrations. Properties of the metal-binding site such as its relative rigidity and solvent accessibility, as well as the type, number, orientation, and protonation state of the metal coordinating ligands, which determine the metal cavity size, geometry, and charge density, affect metal ion selectivity. In several cases, the host protein alone is not able to withstand attacks from biogenic or alien metal cations, which could displace the cognate metal cofactor from the binding site. Whereas the metal-ligand interaction energy becomes less favorable in going down a main group, it becomes more favorable in going across a row in the periodic table, as the net positive charge on the metal increases, yet monovalent ions can still displace divalent ions in certain proteins.


Yip S.,Academia Sinica, Taiwan
Annual Review of Condensed Matter Physics | Year: 2014

Physics of noncentrosymmetric superconductors is reviewed. We explain the mixing between singlet and triplet superconducting order parameters when parity symmetry is absent. Some exotic properties are summarized, including magnetoelectric effects, the helical phase, topological properties, and unusual surface states. © Copyright 2014 by Annual Reviews. All rights reserved.


Yang J.Y.,Academia Sinica, Taiwan
Nature communications | Year: 2013

Eukaryotic cells maintain mitochondrial integrity through mitophagy, an autophagic process by which dysfunctional mitochondria are selectively sequestered into double-layered membrane structures, termed phagophores, and delivered to lysosomes for degradation. Here we show that small fragments of parkin-labelled mitochondria at omegasome-marked sites are engulfed by autophagic membranes one at a time. Using a light-activation scheme to impair long mitochondrial tubules, we demonstrate that sites undergoing bit-by-bit mitophagy display preferential ubiquitination, and are situated where parkin-labelled mitochondrial tubules and endoplasmic reticulum intersect. Our observations suggest contact regions between the endoplasmic reticulum and impaired mitochondria are initiation sites for local LC3 recruitment and mitochondrial remodelling that support bit-by-bit, parkin-mediated mitophagy. These results help in understanding how cells manage to fit large and morphologically heterogeneous mitochondria into micron-sized autophagic membranes during mitophagy.


Wu S.-H.,Academia Sinica, Taiwan
Annual Review of Plant Biology | Year: 2014

Depending on the environment a young seedling encounters, the developmental program following seed germination could be skotomorphogenesis in the dark or photomorphogenesis in the light. Light signals are interpreted by a repertoire of photoreceptors followed by sophisticated gene expression networks, eventually resulting in developmental changes. The expression and functions of photoreceptors and key signaling molecules are highly coordinated and regulated at multiple levels of the central dogma in molecular biology. Light activates gene expression through the actions of positive transcriptional regulators and the relaxation of chromatin by histone acetylation. Small regulatory RNAs help attenuate the expression of light-responsive genes. Alternative splicing, protein phosphorylation/dephosphorylation, the formation of diverse transcriptional complexes, and selective protein degradation all contribute to proteome diversity and change the functions of individual proteins. Copyright © 2014 by Annual Reviews.


Protein palmitoylation has emerged as an important mechanism for regulating protein trafficking, stability, and protein-protein interactions; however, its relevance to disease processes is not clear. Using a genome-wide, phenotype driven N-ethyl-N-nitrosourea-mediated mutagenesis screen, we identified mice with failure to thrive, shortened life span, skin and hair abnormalities including alopecia, severe osteoporosis, and systemic amyloidosis (both AA and AL amyloids depositions). Whole-genome homozygosity mapping with 295 SNP markers and fine mapping with an additional 50 SNPs localized the disease gene to chromosome 7 between 53.9 and 56.3 Mb. A nonsense mutation (c.1273A>T) was located in exon 12 of the Zdhhc13 gene (Zinc finger, DHHC domain containing 13), a gene coding for palmitoyl transferase. The mutation predicted a truncated protein (R425X), and real-time PCR showed markedly reduced Zdhhc13 mRNA. A second gene trap allele of Zdhhc13 has the same phenotypes, suggesting that this is a loss of function allele. This is the first report that palmitoyl transferase deficiency causes a severe phenotype, and it establishes a direct link between protein palmitoylation and regulation of diverse physiologic functions where its absence can result in profound disease pathology. This mouse model can be used to investigate mechanisms where improper palmitoylation leads to disease processes and to understand molecular mechanisms underlying human alopecia, osteoporosis, and amyloidosis and many other neurodegenerative diseases caused by protein misfolding and amyloidosis.


The functional activities of the tumor suppressor promyelocytic leukemia protein (PML) are mostly associated with its nuclear location. In the present study, we discovered an unexpected role of PML in NLRP3 inflammasome activation. In PML-deficient macrophages, the production of IL-1β was strongly impaired. The expression of pro-IL-1β, NLRP3, ASC, and procaspase-1 was not affected in Pml(-/-) macrophages. PML deficiency selectively reduced the processing of procaspase-1. We further showed that PML is required for the assembly of the NLRP3 inflammasome in reconstitution experiment. All PML isoforms were capable of stimulating NLRP3 inflammasome activation. In Pml(-/-) macrophages, the generation of reactive oxygen species and release of mitochondrial DNA were decreased. The involvement of PML in inflammasome activation constitutes an important activity of PML and reveals a new mechanism underlying the inflammasome activation. In addition, downregulation of PML by arsenic trioxide suppressed monosodium urate (MSU)-induced IL-1β production, suggesting that targeting to PML could be used to treat NLRP3 inflammasome-associated diseases.


Chiou T.-J.,Academia Sinica, Taiwan | Lin S.-I.,Academia Sinica, Taiwan
Annual Review of Plant Biology | Year: 2011

Plants acquire phosphorus in the form of phosphate (Pi), the concentration of which is often limited for plant uptake. Plants have developed diverse responses to conserve and remobilize internal Pi and to enhance Pi acquisition to secure them against Pi deficiency. These responses are achieved by the coordination of an elaborate signaling network comprising local and systemic machineries. Recent advances have revealed several important components involved in this network. Pi functions as a signal to report its own availability. miR399 and sugars act as systemic signals to regulate responses occurring in roots. Hormones also play crucial roles in modulating gene expression and in altering root system architecture. Transcription factors function as a hub to perceive the signals and to elicit steady outputs. In this review, we outline the current knowledge on this subject and present hypotheses pertaining to other potential signals and to the organization and coordination of signaling. Copyright © 2011 by Annual Reviews. All rights reserved.


LISE is a web server for a novel method for predicting small molecule binding sites on proteins. It differs from a number of servers currently available for such predictions in two aspects. First, rather than relying on knowledge of similar protein structures, identification of surface cavities or estimation of binding energy, LISE computes a score by counting geometric motifs extracted from sub-structures of interaction networks connecting protein and ligand atoms. These network motifs take into account spatial and physicochemical properties of ligand-interacting protein surface atoms. Second, LISE has now been more thoroughly tested, as, in addition to the evaluation we previously reported using two commonly used small benchmark test sets and targets of two community-based experiments on ligand-binding site predictions, we now report an evaluation using a large non-redundant data set containing >2000 protein-ligand complexes. This unprecedented test, the largest ever reported to our knowledge, demonstrates LISE's overall accuracy and robustness. Furthermore, we have identified some hard to predict protein classes and provided an estimate of the performance that can be expected from a state-of-the-art binding site prediction server, such as LISE, on a proteome scale. The server is freely available at http://lise.ibms.sinica.edu.tw.


Chalker D.L.,Washington University in St. Louis | Yao M.-C.,Academia Sinica, Taiwan
Annual Review of Genetics | Year: 2011

Ciliated protozoa extensively remodel their somatic genomes during nuclear development, fragmenting their chromosomes and removing large numbers of internal eliminated sequences (IESs). The sequences eliminated are unique and repetitive DNAs, including transposons. Recent studies have identified transposase proteins that appear to have been domesticated and are used by these cells to eliminate DNA not wanted in the somatic macronucleus. This DNA elimination process is guided by meiotically produced small RNAs, generated in the germline nucleus, that recognize homologous sequences leading to their removal. These scan RNAs are found in complexes with PIWI proteins. Before they search the developing genome for IESs to eliminate, they scan the parental somatic nucleus and are removed from the pool if they match homologous sequences in that previously reorganized genome. In Tetrahymena, the scan RNAs target heterochromatin modifications to mark IESs for elimination. This DNA elimination pathway in ciliates shares extensive similarity with piRNA-mediated silencing of metazoans and highlights the remarkable ability of homologous RNAs to shape developing genomes. © 2011 by Annual Reviews. All rights reserved.


Matzke M.A.,Academia Sinica, Taiwan | Mosher R.A.,University of Arizona
Nature Reviews Genetics | Year: 2014

RNA-directed DNA methylation (RdDM) is the major small RNA-mediated epigenetic pathway in plants. RdDM requires a specialized transcriptional machinery that comprises two plant-specific RNA polymerases-Pol IV and Pol V-and a growing number of accessory proteins, the functions of which in the RdDM mechanism are only partially understood. Recent work has revealed variations in the canonical RdDM pathway and identified factors that recruit Pol IV and Pol V to specific target sequences. RdDM, which transcriptionally represses a subset of transposons and genes, is implicated in pathogen defence, stress responses and reproduction, as well as in interallelic and intercellular communication. © 2014 Macmillan Publishers Limited. All rights reserved.

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