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Karen Druart, Julien Bigot, Edouard Audit, Thomas Simonson
Multistate protein design explores sidechain mutations with the backbone allowed to sample a small, predetermined library of conformations. To achieve Boltzmann sampling of sequences and conformations, we use a hybrid Monte Carlo (MC) scheme: a trial hop between backbone models is followed by a short MC segment where sidechain rotamers adjust to the new backbone, before applying a Metropolis-like acceptance test. The theoretical form and a practical approximation for the acceptance test are derived. We then compute backbone conformational free energies for two SH2 and SH3 proteins using different routes and protocols, and verify that for simple test problems, the free energy behaves like a state function, a hallmark of Boltzmann sampling...
October 24, 2016: Journal of Chemical Theory and Computation
Takashi Dejima, Kenjiro Imada, Ario Takeuchi, Masaki Shiota, Jeffrey Leong, Tabitha Tombe, Kevin Tam, Ladan Fazli, Seiji Naito, Martin E Gleave, Christopher J Ong
BACKGROUND: LIM and SH3 domain protein 1 (LASP1) has been implicated in several human malignancies and has been shown to predict PSA recurrence in prostate cancer. However, the anti-tumor effect of LASP1 knockdown and the association between LASP1 and the androgen receptor (AR) remains unclear. The aim of this study is to clarify the significance of LASP1 as a target for prostate cancer, and to test the effect of silencing LASP1 in vivo using antisense oligonucleotides (ASO). METHODS: A tissue microarray (TMA) was performed to characterize the differences in LASP1 expression in prostate cancer treated after hormone deprivation therapy...
October 24, 2016: Prostate
Michael Chalick, Oded Jacobi, Edward Pichinuk, Christian Garbar, Armand Bensussan, Alan Meeker, Ravit Ziv, Tania Zehavi, Nechama I Smorodinsky, John Hilkens, Franz-Georg Hanisch, Daniel B Rubinstein, Daniel H Wreschner
Translation of mRNA in alternate reading frames (ARF) is a naturally occurring process heretofore underappreciated as a generator of protein diversity. The MUC1 gene encodes MUC1-TM, a signal-transducing trans-membrane protein highly expressed in human malignancies. Here we show that an AUG codon downstream to the MUC1-TM initiation codon initiates an alternate reading frame thereby generating a novel protein, MUC1-ARF. MUC1-ARF, like its MUC1-TM 'parent' protein, contains a tandem repeat (VNTR) domain. However, the amino acid sequence of the MUC1-ARF tandem repeat as well as N- and C- sequences flanking it differ entirely from those of MUC1-TM...
2016: PloS One
Can-Zhao Liu, Xiang-Yu Li, Ren-Hong Du, Min Gao, Ming-Ming Ma, Fei-Ya Li, Er-Wen Huang, Hong-Shuo Sun, Guan-Lei Wang, Yong-Yuan Guan
BACKGROUND: Previous research has demonstrated that ClC-3 is responsible for volume-regulated Cl(-)current (ICl.vol) in vascular smooth muscle cells (VSMCs). However, it is still not clear whether and how ClC-3 is transported to cell membranes, resulting in alteration ofICl.vol.Methods and Results:Volume-regulated chloride current (ICl.vol) was recorded by whole-cell patch clamp recording, and Western blotting and co-immunoprecipitation were performed to examine protein expression and protein-protein interaction...
October 19, 2016: Circulation Journal: Official Journal of the Japanese Circulation Society
Martin Sztacho, Sandra Segeletz, Maria Arantzazu Sanchez-Fernandez, Cornelia Czupalla, Christian Niehage, Bernard Hoflack
Bone resorption in vertebrates relies on the ability of osteoclasts to assemble F-actin-rich podosomes that condense into podosomal belts, forming sealing zones. Sealing zones segregate bone-facing ruffled membranes from other membrane domains, and disassemble when osteoclasts migrate to new areas. How podosome/sealing zone dynamics is regulated remains unknown. We illustrate the essential role of the membrane scaffolding F-BAR-Proline-Serine-Threonine Phosphatase Interacting Proteins (PSTPIP) 1 and 2 in this process...
2016: PloS One
Nils Rademacher, Bettina Schmerl, Jennifer A Lardong, Markus C Wahl, Sarah A Shoichet
At neuronal synapses, multiprotein complexes of trans-synaptic adhesion molecules, scaffold proteins and neurotransmitter receptors assemble to essential building blocks required for synapse formation and maintenance. Here we describe a novel role for the membrane-associated guanylate kinase (MAGUK) protein MPP2 (MAGUK p55 subfamily member 2) at synapses of rat central neurons. Through interactions mediated by its C-terminal SH3-GK domain module, MPP2 binds to the abundant postsynaptic scaffold proteins PSD-95 and GKAP and localises to postsynaptic sites in hippocampal neurons...
October 19, 2016: Scientific Reports
Leonardo A Gómez, Francisco I Alvarez, Pablo A Fernández, Manuel R Flores, Raúl E Molina, Roberto F Coloma, Angel A Oñate
Immunogenicity induced by recombinant plasmids based on the BAB1_0267 and BAB1_0270 open reading frames (ORFs) of Brucella abortus 2308 was evaluated. Bioinformatics analyses indicate that the BAB1_0267 and BAB1_0270 ORFs encode a protein with a SH3 domain and a Zn-dependent metalloproteinase, respectively. Both ORFs have important effects on intracellular survival and replication of B. abortus 2308, mediated via professional and non-professional phagocytic cells. Our results show that immunization with the recombinant plasmid based on the BAB1_0267 ORF significantly increases the production of IgG1, levels of IFN-γ and the lymphoproliferative response of splenocytes...
2016: Frontiers in Cellular and Infection Microbiology
Jyoti R Misra, Kenneth D Irvine
The protocadherins Dachsous and Fat initiate a signaling pathway that controls growth and planar cell polarity by regulating the membrane localization of the atypical myosin Dachs. How Dachs is regulated by Fat signaling has remained unclear. Here we identify the vamana gene as playing a crucial role in regulating membrane localization of Dachs and in linking Fat and Dachsous to Dachs regulation. Vamana, an SH3-domain-containing protein, physically associates with and co-localizes with Dachs and promotes its membrane localization...
October 7, 2016: Developmental Cell
Cunzhen Zhang, Fenghua Liu, Haiyang Chen, Nan Li, Zaili Luo, Weixing Guo, Dandan Huang, Shanhua Tang, Honggang Wang, Shuqun Cheng, Zhong Li, Hongyang Wang
Tumor metastasis is the process by which tumor cells disseminate from tumors and enter nearby and distant microenvironments for new colonization. Bif-1 (BAX-interacting factor 1), which has a BAR domain and an SH3 domain, has been reported to be involved in cell growth, apoptosis and autophagy. However, the influence of Bif-1 on metastasis has been less studied. To understand the role of Bif-1 in metastasis, we studied the expression levels of Bif-1 in human HCC specimens using immunohistochemistry, a tissue microarray and quantitative PCR...
October 11, 2016: Clinical & Experimental Metastasis
Maggy Hologne, François-Xavier Cantrelle, Gwladys Riviere, Florence Guillière, Xavier Trivelli, Olivier Walker
AMSH is one of the deubiquitinating enzymes associated in the regulation of endocytic cargo trafficking. It shows an exquisite selectivity for Lys63-linked polyubiquitin chains that are the main chains involved in cargo sorting. The first step requires the ESCRT-0 complex that comprises the STAM and Hrs proteins. Previous studies have shown that the presence of the STAM protein increases the efficiency of Lys63-linked polyubiquitin chain cleavage by AMSH, one of the deubiquitinating enzyme involved in lysosomal degradation...
October 7, 2016: Journal of Molecular Biology
Mikolai Fajer, Yilin Meng, Benoit Roux
Tyrosine kinases are important cellular signaling allosteric enzymes that regulate cell growth, proliferation, metabolism, differentiation and migration. Their activity must be tightly regulated, and disruption of this regulation can lead to a variety of diseases, particularly cancer. The non-receptor tyrosine kinase c-Src, a prototypical model system and a representative member of the Src-family, functions as complex multi-domain allosteric molecular switches comprising SH2 and SH3 domains regulating the activity of the catalytic domain...
October 7, 2016: Journal of Physical Chemistry. B
Yoe-Sik Bae, Ha Young Lee, Young Su Jung, Mingyu Lee, Pann-Ghill Suh
Among the phospholipase C (PLC) isoforms, PLCγ not only has unique structural characteristics in terms of harboring SH2 and SH3 domains but also mediates growth factor-induced signaling pathways. PLCγ isoforms are expressed in several innate immune cell types, including macrophages, natural killer cells, mast cells, and neutrophils. Stimulation of Fc receptor or integrin in innate immune cells induces PLCγ activation, which leads to phosphoinositide hydrolysis and calcium increase. The products of PLCγ activity mediate the innate immune response by regulating respiratory burst, phagocytosis, cell adhesion, and cell migration...
September 27, 2016: Advances in Biological Regulation
Le-Le Wang, Lei Wang, Xiao-Ying Wang, Di Shang, Sheng-Jie Yin, Li-Li Sun, Hong-Bo Ji
The present study aims to investigate the effects of microRNA-218 (miR-218) on the proliferation, migration, invasion, and apoptosis of gastric cancer (GC) cells by targeting LIM and SH3 domain protein 1 (LASP1). The GC cells in the logarithmic phase were selected and divided into five groups: the blank group, negative control (NC) group, miR-218 inhibitors group, miR-218 inhibitors + siLASP1 group, and miR-218 mimics + siLASP1 group. The miR-218 expression in each group was also detected by qRT-PCR. The CCK8 assay, Transwell migration, and invasion assays and flow cytometry were performed to determine the effects of miR-218 on cell proliferation, migration, invasion, and apoptosis of GC cells...
September 30, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Susanna Krapp, Eva Greiner, Bushra Amin, Uwe Sonnewald, Björn Krenz
Stress granules (SGs) are structures within cells that regulate gene expression during stress response, e.g. viral infection. In mammalian cells assembly of SGs is dependent on the Ras-GAP SH3-domain-binding protein (G3BP). The C-terminal domain of the viral nonstructural protein 3 (nsP3) of Semliki Forest virus (SFV) forms a complex with mammalian G3BP and sequesters it into viral RNA replication complexes in a manner that inhibits the formation of SGs. The binding domain of nsP3 to HsG3BP was mapped to two tandem 'FGDF' repeat motifs close to the C-terminus of the viral proteins...
September 29, 2016: Virus Research
Lushen Li, Hongyu Liu, Shaneen S Baxter, Ning Gu, Min Ji, Xi Zhan
The family of inverse BAR (I-BAR) domain proteins participates in a range of cellular processes associated with membrane dynamics and consists of five distinct members. Three of the I-BAR proteins, including insulin receptor tyrosine kinase substrate (IRTKS), contain an SH3 domain near their C-termini. Yet, the function of the SH3 domain of IRTKS remains uncharacterized. Here we report that in contrast to MIM, which is a prototype of I-BAR proteins and does not contain an SH3 domain, IRTKS promoted serum-induced cell migration along with enhanced phosphorylation of mitogen activated kinases Erk1/2 and p38, and activation of small GTPases Rac1 and Cdc42...
October 28, 2016: Biochemical and Biophysical Research Communications
Radu Huculeci, Elisa Cilia, Agatha Lyczek, Lieven Buts, Klaartje Houben, Markus A Seeliger, Nico van Nuland, Tom Lenaerts
Src kinase activity is controlled by various mechanisms involving a coordinated movement of kinase and regulatory domains. Notwithstanding the extensive knowledge related to the backbone dynamics, little is known about the more subtle side-chain dynamics within the regulatory domains and their role in the activation process. Here, we show through experimental methyl dynamic results and predicted changes in side-chain conformational couplings that the SH2 structure of Fyn contains a dynamic network capable of propagating binding information...
September 28, 2016: Structure
Yifei Zhang, Xing Wang, Hitoshi Matakatsu, Richard Fehon, Seth S Blair
Much of the Hippo and planar cell polarity (PCP) signaling mediated by the Drosophila protocadherin Fat depends on its ability to change the subcellular localization, levels and activity of the unconventional myosin Dachs. To better understand this process, we have performed a structure-function analysis of Dachs, and used this to identify a novel and important mediator of Fat and Dachs activities, a Dachs-binding SH3 protein we have named Dlish. We found that Dlish is regulated by Fat and Dachs, that Dlish also binds Fat and the Dachs regulator Approximated, and that Dlish is required for Dachs localization, levels and activity in both wild type and fat mutant tissue...
October 3, 2016: ELife
Yoko Shigeno-Nakazawa, Takuma Kasai, Sewon Ki, Elina Kostyanovskaya, Jana Pawlak, Junya Yamagishi, Noriaki Okimoto, Makoto Taiji, Mariko Okada, Jody Westbrook, Yoko Satta, Takanori Kigawa, Akira Imamoto
CRK and CRKL adapter proteins play essential roles in development and cancer through their SRC homology 2 and 3 (SH2 and SH3) domains. To gain insight into the origin of their shared functions, we have investigated their evolutionary history. We propose a term, crk/crkl ancestral (crka), for orthologs in invertebrates before the divergence of CRK and CRKL in the vertebrate ancestor. We have isolated two orthologs expressed in the choanoflagellate Monosiga brevicollis, a unicellular relative to the metazoans...
September 30, 2016: Scientific Reports
Weiwei Song, Hengyu Zhao, Zhongqi Cui, Xiaoyu Ma, Wenwen Zhang, Di Wang, Anqi Liu, Lijie Yuan
Glioblastoma multiforme (GBM) is an aggressive tumor of the central nervous system characterized by high rates of recurrence, morbidity, and mortality. This study investigated the antitumor effects of an apoptin-derived peptide (ADP) on glioma cells and explored the underlying mechanisms. The U251, U87, and C6 glioma cell lines were used in the present study, and the expression of p-Akt, Akt, and MMP-9 was determined through Western blotting, quantitative real-time PCR, and hematoxylin and eosin (HE) staining...
September 29, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Yoshihiro Ishikawa, Shinya Ito, Kazuhiro Nagata, Lynn Y Sakai, Hans Peter Bächinger
Extracellular matrix (ECM) proteins are biosynthesized in the rough endoplasmic reticulum (rER) and transported via the Golgi apparatus to the extracellular space. The coat protein complex II (COPII) transport vesicles are approximately 60-90 nm in diameter. However, several ECM molecules are much larger, up to several hundreds of nanometers. Therefore, special COPII vesicles are required to coat and transport these molecules. Transmembrane Protein Transport and Golgi Organization 1 (TANGO1) facilitates loading of collagens into special vesicles...
October 11, 2016: Proceedings of the National Academy of Sciences of the United States of America
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