Digital Commons Network^™

Medicinal Plants: A Public Resource For Metabolomics And Hypothesis Development, Eve Syrkin Wurtele, Joe Chappell, A. Daniel Jones, Mary Dawn Celiz, Nick Ransom, Manhoi Hur, Ludmila Rizshsky, Matthew Crispin, Philip Dixon, Jia Liu, Mark P. Widrlechner, Basil J. Nikolau

Molecular and Cellular Biochemistry Faculty Publications

Specialized compounds from photosynthetic organisms serve as rich resources for drug development. From aspirin to atropine, plant-derived natural products have had a profound impact on human health. Technological advances provide new opportunities to access these natural products in a metabolic context. Here, we describe a database and platform for storing, visualizing and statistically analyzing metabolomics data from fourteen medicinal plant species. The metabolomes and associated transcriptomes (RNAseq) for each plant species, gathered from up to twenty tissue/organ samples that have experienced varied growth conditions and developmental histories, were analyzed in parallel. Three case studies illustrate different ways that the data …

Plant Polyadenylation Factors: Conservation And Variety In The Polyadenylation Complex In Plants, Arthur G. Hunt, Denghui Xing, Qingshun Q. Li

Plant and Soil Sciences Faculty Publications

BACKGROUND: Polyadenylation, an essential step in eukaryotic gene expression, requires both cis-elements and a plethora of trans-acting polyadenylation factors. The polyadenylation factors are largely conserved across mammals and fungi. The conservation seems also extended to plants based on the analyses of Arabidopsis polyadenylation factors. To extend this observation, we systemically identified the orthologs of yeast and human polyadenylation factors from 10 plant species chosen based on both the availability of their genome sequences and their positions in the evolutionary tree, which render them representatives of different plant lineages.

RESULTS: The evolutionary trajectories revealed several interesting features of plant polyadenylation factors. …

Biochemical Pathways In Cancer, Eun-Kyoung Yim Breuer, Mandi M. Murph, Rolf J. Craven

Pharmacology and Nutritional Sciences Faculty Publications

No abstract.

Controls Of Nucleosome Positioning In The Human Genome, Daniel J. Gaffney, Graham Mcvicker, Athma A. Pai, Yvonne N. Fondufe-Mittendorf, Noah Lewellen, Katelyn Michelini, Jonathan Widom, Yoav Gilad, Jonathan K. Pritchard

Molecular and Cellular Biochemistry Faculty Publications

Nucleosomes are important for gene regulation because their arrangement on the genome can control which proteins bind to DNA. Currently, few human nucleosomes are thought to be consistently positioned across cells; however, this has been difficult to assess due to the limited resolution of existing data. We performed paired-end sequencing of micrococcal nuclease-digested chromatin (MNase-seq) from seven lymphoblastoid cell lines and mapped over 3.6 billion MNase-seq fragments to the human genome to create the highest-resolution map of nucleosome occupancy to date in a human cell type. In contrast to previous results, we find that most nucleosomes have more consistent positioning …

Open Release Of Male Mosquitoes Infected With A Wolbachia Biopesticide: Field Performance And Infection Containment, Linda O'Connor, Catherine Plichart, Ayo Cheong Sang, Corey L. Brelsfoard, Hervé C. Bossin, Stephen L. Dobson

Entomology Faculty Publications

BACKGROUND: Lymphatic filariasis (LF) is a globally significant disease, with 1.3 billion persons in 83 countries at risk. A coordinated effort of administering annual macrofilaricidal prophylactics to the entire at-risk population has succeeded in impacting and eliminating LF transmission in multiple regions. However, some areas in the South Pacific are predicted to persist as transmission sites, due in part to the biology of the mosquito vector, which has led to a call for additional tools to augment drug treatments. Autocidal strategies against mosquitoes are resurging in the effort against invasive mosquitoes and vector borne disease, with examples that include field …

Toward The Beginning Of Time: Circadian Rhythms In Metabolism Precede Rhythms In Clock Gene Expression In Mouse Embryonic Stem Cells, Jiffin K. Paulose, Edmund B. Rucker Iii, Vincent M. Cassone

Biology Faculty Publications

The appearance, progression, and potential role for circadian rhythms during early development have previously focused mainly on the suprachiasmatic nucleus (SCN) and peri- and postnatal expression of canonical clock genes. More recently, gene expression studies in embryonic stem cells have shown that some clock genes are expressed in undifferentiated cells; however rhythmicity was only established when cells are directed toward a neural fate. These studies also concluded that a functional clock is not present in ESCs, based solely on their gene expression. The null hypothesis underlying the present study is that embryonic stem cells become rhythmic in both clock gene …

Targeting Astrocytes Ameliorates Neurologic Changes In A Mouse Model Of Alzheimer's Disease, Jennifer L. Furman, Diana M. Sama, John C. Gant, Tina L. Beckett, M. Paul Murphy, Adam D. Bachstetter, Linda J. Van Eldik, Christopher M. Norris

Pharmacology and Nutritional Sciences Faculty Publications

Astrocytes are the most abundant cell type in the brain and play a critical role in maintaining healthy nervous tissue. In Alzheimer's disease (AD) and most other neurodegenerative disorders, many astrocytes convert to a chronically "activated" phenotype characterized by morphologic and biochemical changes that appear to compromise protective properties and/or promote harmful neuroinflammatory processes. Activated astrocytes emerge early in the course of AD and become increasingly prominent as clinical and pathological symptoms progress, but few studies have tested the potential of astrocyte-targeted therapeutics in an intact animal model of AD. Here, we used adeno-associated virus (AAV) vectors containing the astrocyte-specific …

Wolbachia Strain Wpip Yields A Pattern Of Cytoplasmic Incompatibility Enhancing A Wolbachia-Based Suppression Strategy Against The Disease Vector Aedes Albopictus, Maurizio Calvitti, Riccardo Moretti, Amanda R. Skidmore, Stephen L. Dobson

Entomology Faculty Publications

BACKGROUND: Cytoplasmic incompatibility (CI) is induced in nature by Wolbachia bacteria, resulting in conditional male sterility. Previous research demonstrated that the two Wolbachia strains (wAlbA and wAlbB) that naturally co-infect the disease vector mosquito Aedes albopictus (Asian tiger mosquito) can be replaced with the wPip Wolbachia strain from Culex pipiens. Since Wolbachia-based vector control strategies depend upon the strength and consistency of CI, a greater understanding is needed on the CI relationships between wPip, wAlbA and wAlbB Wolbachia in Ae. albopictus.

METHODS: This work consisted of a collaborative series of crosses carried out in Italy and in US to study …

Physiological Epicotyl Dormancy And Recalcitrant Storage Behaviour In Seeds Of Two Tropical Fabaceae (Subfamily Caesalpinioideae) Species, K. M. G. Gehan Jayasuriya, Asanga S. T. B. Wijetunga, Jerry M. Baskin, Carol C. Baskin

Biology Faculty Publications

BACKGROUND AND AIMS: Physiological epicotyl dormancy in which the epicotyl elongates inside the seed before the shoot emerges has been reported for only a few tropical rainforest species, all of which are trees that produce recalcitrant seeds. In studies on seeds of Fabaceae in Sri Lanka, we observed a considerable time delay in shoot emergence following root emergence in seeds of the introduced caesalpinioid legumes Brownea coccinea and Cynometra cauliflora. Thus, our aim was to determine if seeds of these two tropical rainforest trees have physiological epicotyl dormancy, and also if they are recalcitrant, i.e. desiccation sensitive.

METHODOLOGY: Fresh seeds …

Mechanism Of Selective Vegf-A Binding By Neuropilin-1 Reveals A Basis For Specific Ligand Inhibition, Matthew W. Parker, Ping Xu, Hou-Fu Guo, Craig W. Vander Kooi

Molecular and Cellular Biochemistry Faculty Publications

Neuropilin (Nrp) receptors function as essential cell surface receptors for the Vascular Endothelial Growth Factor (VEGF) family of proangiogenic cytokines and the semaphorin 3 (Sema3) family of axon guidance molecules. There are two Nrp homologues, Nrp1 and Nrp2, which bind to both overlapping and distinct members of the VEGF and Sema3 family of molecules. Nrp1 specifically binds the VEGF-A_164/5 isoform, which is essential for developmental angiogenesis. We demonstrate that VEGF-A specific binding is governed by Nrp1 residues in the b1 coagulation factor domain surrounding the invariant Nrp C-terminal arginine binding pocket. Further, we show that Sema3F does not display …

Indole Compounds And Their Use As Radiation Sensitizing Agents And Chemotherapeutic Agents, Peter A. Crooks, Thirupathi R. Yerramreddy, Narsimha Reddy Penthala, Michael L. Freeman, Sekhar R. Konjeti

Pharmaceutical Sciences Faculty Patents

Indole derivatives that are useful in the treatment of cancer as a chemotherapeutic agent or radiosensitizing agent.

Load-Relaxation Properties Of The Human Trunk In Response To Prolonged Flexion: Measuring And Modeling The Effect Of Flexion Angle, Nima Toosizadeh, Maury A. Nussbaum, Babak Bazrgari, Michael L. Madigan

Biomedical Engineering Faculty Publications

Experimental studies suggest that prolonged trunk flexion reduces passive support of the spine. To understand alterations of the synergy between active and passive tissues following such loadings, several studies have assessed the time-dependent behavior of passive tissues including those within spinal motion segments and muscles. Yet, there remain limitations regarding load-relaxation of the lumbar spine in response to flexion exposures and the influence of different flexion angles. Ten healthy participants were exposed for 16 min to each of five magnitudes of lumbar flexion specified relative to individual flexion-relaxation angles (i.e., 30, 40, 60, 80, and 100%), during which lumbar flexion …

Forage News [2012-11], Department Of Plant And Soil Sciences, University Of Kentucky

Forage News

• Kentucky Grazing Conference
• KFGC Presents Awards
• Alfalfa Intensive Training Seminar
• Kentuckian Featured at National Hay Convention
• AFGC Conference in Covington
• Kentucky's 2012 National Forage Spokesman to speak at Farm Bureau Forage Commodity Conference
• Dr. Peter Ballerstedt to Speak at Forages at KCA During the KCA Convention
• Neutral Detergent Fiber Digestibility (NDFD): A Good Predictor of Forage Quality
• Where Does Nitrogen Fertilizer Come From?
• The Cost of Pasture vs. Hay

Longitudinal Documentation Of Serum Cartilage Oligomeric Matrix Protein And Patient-Reported Outcomes In Collegiate Soccer Athletes Over The Course Of An Athletic Season, Johanna M. Hoch, Carl G. Mattacola, Heather M. Bush, Jennifer M. Medina Mckeon, Timothy E. Hewett, Christian Lattermann

Physical Therapy Faculty Publications

BACKGROUND: Serum cartilage oligomeric matrix protein (sCOMP) is a biomarker for cartilage degradation. Patient-reported outcomes (PRO) are used to document postinjury recovery and may be used to prospectively identify changes in the course of a season. It is unknown what effect intense, continuous physical activity has on sCOMP levels and PRO values in athletes over the duration of a soccer season.

HYPOTHESIS/PURPOSE: The purpose of this study was to longitudinally document sCOMP levels and to determine whether changes in PROs occur in collegiate soccer athletes during a season. The hypotheses tested were that sCOMP levels and PRO scores would remain …

Multifactorial Patterns Of Gene Expression In Colonic Epithelial Cells Predict Disease Phenotypes In Experimental Colitis, Aubrey Leigh Frantz, Maria E. C. Bruno, Eric William Rogier, Halide Tuna, Donald A. Cohen, Subbarao Bondada, Ralph Lakshman Chelvarajan, J. Anthony Brandon, C. Darrell Jennings, Charlotte S. Kaetzel

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Background— The pathogenesis of inflammatory bowel disease (IBD) is complex and the need to identify molecular biomarkers is critical. Epithelial cells play a central role in maintaining intestinal homeostasis. We previously identified five “signature” biomarkers in colonic epithelial cells (CEC) that are predictive of disease phenotype in Crohn's disease. Here we investigate the ability of CEC biomarkers to define the mechanism and severity of intestinal inflammation.

Methods— We analyzed the expression of RelA, A20, pIgR, tumor necrosis factor (TNF), and macrophage inflammatory protein (MIP)-2 in CEC of mice with dextran sodium sulfate (DSS) acute colitis or T-cell-mediated chronic colitis. …

Noninvasive Optical Characterization Of Muscle Blood Flow, Oxygenation, And Metabolism In Women With Fibromyalgia, Yu Shang, Katelyn Gurley, Brock Symons, Douglas Long, Ratchakrit Srikuea, Leslie J. Crofford, Charlotte A. Peterson, Guoqiang Yu

Biomedical Engineering Faculty Publications

INTRODUCTION: Women with fibromyalgia (FM) have symptoms of increased muscular fatigue and reduced exercise tolerance, which may be associated with alterations in muscle microcirculation and oxygen metabolism. This study used near-infrared diffuse optical spectroscopies to noninvasively evaluate muscle blood flow, blood oxygenation and oxygen metabolism during leg fatiguing exercise and during arm arterial cuff occlusion in post-menopausal women with and without FM.

METHODS: Fourteen women with FM and twenty-three well-matched healthy controls participated in this study. For the fatiguing exercise protocol, the subject was instructed to perform 6 sets of 12 isometric contractions of knee extensor muscles with intensity steadily …

Regional Variation In Aortic At1b Receptor Mrna Abundance Is Associated With Contractility But Unrelated To Atherosclerosis And Aortic Aneurysms, Aruna Poduri, A. Phillip Owens, Deborah A. Howatt, Jessica J. Moorleghen, Anju Balakrishnan, Lisa A. Cassis, Alan Daugherty

Pharmacology and Nutritional Sciences Faculty Publications

BACKGROUND: Angiotensin II (AngII), the main bioactive peptide of the renin angiotensin system, exerts most of its biological actions through stimulation of AngII type 1 (AT1) receptors. This receptor is expressed as 2 structurally similar subtypes in rodents, termed AT1a and AT1b. Although AT1a receptors have been studied comprehensively, roles of AT1b receptors in the aorta have not been defined.

METHODOLOGY/RESULTS: We initially compared the regional distribution of AT1b receptor mRNA with AT1a receptor mRNA in the aorta. mRNA abundance of both subtypes increased from the proximal to the distal aorta, with the greatest abundance in the infra-renal region. Corresponding …

Tris-Quarternary Ammonium Salts And Methods For Modulating Neuronal Nicotinic Acetylcholine Receptors, Peter Crooks, Linda P. Dwoskin, Roger Papke, Guangrong Zheng, Sangeetha Sumithran

Pharmaceutical Sciences Faculty Patents

Provided are tris-quaternary ammonium compounds which are modulators of nicotinic acetylocholine receptors. Also provided are methods of using the compounds for modulating the function of a nicotinic acetylcholine receptor, and for the prevention and/or treatment of central nervous system disorders, substance use and/or abuse and or gastrointestinal tract disorders.

Escherichia Coli Recg Functionally Suppresses Human Bloom Syndrome Phenotypes, Michael W. Killen, Dawn M. Stults, William A. Wilson, Andrew J. Pierce

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Defects in the human BLM gene cause Bloom syndrome, notable for early development of tumors in a broad variety of tissues. On the basis of sequence similarity, BLM has been identified as one of the five human homologs of RecQ from Escherichia coli. Nevertheless, biochemical characterization of the BLM protein indicates far greater functional similarity to the E. coli RecG protein and there is no known RecG homolog in human cells. To explore the possibility that the shared biochemistries of BLM and RecG may represent an example of convergent evolution of cellular function where in humans BLM has evolved to …

Rod Microglia: Elongation, Alignment, And Coupling To Form Trains Across The Somatosensory Cortex After Experimental Diffuse Brain Injury, Jenna M. Ziebell, Samuel E. Taylor, Tuoxin Cao, Jordan L. Harrison, Jonathan Lifshitz

Neuroscience Faculty Publications

BACKGROUND: Since their discovery, the morphology of microglia has been interpreted to mirror their function, with ramified microglia constantly surveying the micro-environment and rapidly activating when changes occur. In 1899, Franz Nissl discovered what we now recognize as a distinct microglial activation state, microglial rod cells (Stäbchenzellen), which he observed adjacent to neurons. These rod-shaped microglia are typically found in human autopsy cases of paralysis of the insane, a disease of the pre-penicillin era, and best known today from HIV-1-infected brains. Microglial rod cells have been implicated in cortical 'synaptic stripping' but their exact role has remained unclear. This is …

Food Insecurity Across The First Five Years: Triggers Of Onset And Exit, Alison Jacknowitz, Taryn W. Morrissey

University of Kentucky Center for Poverty Research Discussion Paper Series

Very low food security among young children is associated with developmental deficiencies. However, little is known about the factors that predict entry into or exit from very low food security during early childhood. This study seeks to: (1) Understand the triggers that explain movements into or out of very low food security among children from birth to age five; (2) Examine the first aim using different definitions of food insecurity. The analysis relies on the Early Childhood Longitudinal Study-Birth Cohort (ECLS-B), a longitudinal, nationally representative dataset of approximately 10,700 children, to estimate linear probability models. Results suggest that residential moves …

Organics In Environmental Ices: Sources, Chemistry, And Impacts, V. F. Mcneill, A. M. Grannas, J. P. D. Abbatt, M. Ammann, P. Ariya, T. Bartels-Rausch, F. Domine, D. J. Donaldson, Marcelo I. Guzman, D. Heger, T. F. Kahan, P. Klán, S. Masclin, C. Toubin, D. Voisin

Chemistry Faculty Publications

The physical, chemical, and biological processes involving organics in ice in the environment impact a number of atmospheric and biogeochemical cycles. Organic material in snow or ice may be biological in origin, deposited from aerosols or atmospheric gases, or formed chemically in situ. In this manuscript, we review the current state of knowledge regarding the sources, properties, and chemistry of organic materials in environmental ices. Several outstanding questions remain to be resolved and fundamental data gathered before an accurate model of transformations and transport of organic species in the cryosphere will be possible. For example, more information is needed regarding …

Double-Stranded Rna-Dependent Protein Kinase Regulates The Motility Of Breast Cancer Cells, Mei Xu, Gang Chen, Siying Wang, Mingjun Liao, Jacqueline A. Frank, Kimberly A. Bower, Zhuo Zhang, Xianglin Shi, Jia Luo

Internal Medicine Faculty Publications

Double-stranded RNA (dsRNA)-dependent protein kinase (PKR) is an interferon-induced protein kinase that plays a central role in the anti-viral process. Due to its pro-apoptotic and anti-proliferative action, there is an increased interest in PKR modulation as an anti-tumor strategy. PKR is overexpressed in breast cancer cells; however, the role of PKR in breast cancer cells is unclear. The expression/activity of PKR appears inversely related to the aggressiveness of breast cancer cells. The current study investigated the role of PKR in the motility/migration of breast cancer cells. The activation of PKR by a synthesized dsRNA (PIC) significantly decreased the motility of …

Cloning, Ligand-Binding, And Temporal Expression Of Ecdysteroid Receptors In The Diamondback Moth, Plutella Xylostella, Baozhen Tang, Wei Dong, Pei Liang, Xuguo Zhou, Xiwu Gao

Entomology Faculty Publications

BACKGROUND: The diamondback moth, Plutella xylostella (L.) (Lepidoptera: Plutellidae), is a devastating pest of cruciferous crops worldwide, and has developed resistance to a wide range of insecticides, including diacylhydrazine-based ecdysone agonists, a highly selective group of molt-accelerating biopesticides targeting the ecdysone receptors.

RESULT: In this study, we cloned and characterized the ecdysone receptors from P. xylostella, including the two isoforms of EcR and a USP. Sequence comparison and phylogenetic analysis showed striking conservations among insect ecdysone receptors, especially between P. xylostella and other lepidopterans. The binding affinity of ecdysteroids to in vitro-translated receptor proteins indicated that PxEcRB isoform bound specifically …

Quercetin Inhibits Angiogenesis Mediated Human Prostate Tumor Growth By Targeting Vegfr- 2 Regulated Akt/Mtor/P70s6k Signaling Pathways, Poyil Pratheeshkumar, Amit Budhraja, Young-Ok Son, Xin Wang, Zhuo Zhang, Songze Ding, Lei Wang, Andrew Hitron, Jeong-Chae Lee, Mei Xu, Gang Chen, Jia Luo, Xianglin Shi

Toxicology and Cancer Biology Faculty Publications

Angiogenesis is a crucial step in the growth and metastasis of cancers, since it enables the growing tumor to receive oxygen and nutrients. Cancer prevention using natural products has become an integral part of cancer control. We studied the antiangiogenic activity of quercetin using ex vivo, in vivo and in vitro models. Rat aortic ring assay showed that quercetin at non-toxic concentrations significantly inhibited microvessel sprouting and exhibited a significant inhibition in the proliferation, migration, invasion and tube formation of endothelial cells, which are key events in the process of angiogenesis. Most importantly, quercetin treatment inhibited ex vivo angiogenesis …

Gene Expression Analysis Of A Murine Model With Pulmonary Vascular Remodeling Compared To End-Stage Ipah Lungs, Kayoko Shimodaira, Yoichiro Okubo, Eri Ochiai, Haruo Nakayama, Harutaka Katano, Megumi Wakayama, Minoru Shinozaki, Takao Ishiwatari, Daisuke Sasai, Naobumi Tochigi, Tetsuo Nemoto, Tsutomu Saji, Katsuhiko Kamei, Kazutoshi Shibuya

Microbiology, Immunology, and Molecular Genetics Faculty Publications

BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) continues to be one of the most serious intractable diseases that might start with activation of several triggers representing the genetic susceptibility of a patient. To elucidate what essentially contributes to the onset and progression of IPAH, we investigated factors playing an important role in IPAH by searching discrepant or controversial expression patterns between our murine model and those previously published for human IPAH. We employed the mouse model, which induced muscularization of pulmonary artery leading to hypertension by repeated intratracheal injection of Stachybotrys chartarum, a member of nonpathogenic and ubiquitous fungus in our …

Gene Expression Patterns Specific To The Regenerating Limb Of The Mexican Axolotl, James R. Monaghan, Antony Athippozhy, Ashley W. Seifert, Sri Putta, Arnold J. Stromberg, Malcolm Maden, David M. Gardiner, Stephen R. Voss

Biology Faculty Publications

Salamander limb regeneration is dependent upon tissue interactions that are local to the amputation site. Communication among limb epidermis, peripheral nerves, and mesenchyme coordinate cell migration, cell proliferation, and tissue patterning to generate a blastema, which will form missing limb structures. An outstanding question is how cross-talk between these tissues gives rise to the regeneration blastema. To identify genes associated with epidermis-nerve-mesenchymal interactions during limb regeneration, we examined histological and transcriptional changes during the first week following injury in the wound epidermis and subjacent cells between three injury types; 1) a flank wound on the side of the animal that …

Cysteine 904 Is Required For Maximal Insulin Degrading Enzyme Activity And Polyanion Activation, Eun Suk Song, Manana Melikishvili, Michael G. Fried, Maria A. Juliano, Luiz Juliano, David W. Rodgers, Louis B. Hersh

Molecular and Cellular Biochemistry Faculty Publications

Cysteine residues in insulin degrading enzyme have been reported as non-critical for its activity. We found that converting the twelve cysteine residues in rat insulin degrading enzyme (IDE) to serines resulted in a cysteine-free form of the enzyme with reduced activity and decreased activation by polyanions. Mutation of each cysteine residue individually revealed cysteine 904 as the key residue required for maximal activity and polyanion activation, although other cysteines affect polyanion binding to a lesser extent. Based on the structure of IDE, Asn 575 was identified as a potential hydrogen bond partner for Cys904 and mutation of this residue also …

Withanolide Compounds As Inhibitors Of Fibrosis And Identification Of Molecular Targets For Anti-Fibrotic Drug Development, Royce Mohan, Paola Bargagna-Mohan

Ophthalmology and Visual Science Faculty Patents

Provided are methods for screening for drugs effective for treating fibrotic conditions. One screening method comprises exposing a cell to a test compound, monitoring the effect of the test compound on the amount or form of a cell molecule, comparing the amount or form of the cell molecule with the result obtained by treatment of the cell with an anti-fibrotic -effective amount of a withanolide compound, and selecting a drug effective for treating a fibrotic disease based on the ability of the test compound to provide the effect obtained by the withanolide compound on the cell molecule. Also provided is …

Fus-Nls/Transportin 1 Complex Structure Provides Insights Into The Nuclear Targeting Mechanism Of Fus And The Implications In Als, Chunyan Niu, Jiayu Zhang, Feng Gao, Liuqing Yang, Minze Jia, Haining Zhu, Weimin Gong

Molecular and Cellular Biochemistry Faculty Publications

The C-terminal nuclear localization sequence of FUsed in Sarcoma (FUS-NLS) is critical for its nuclear import mediated by transportin (Trn1). Familial amyotrophic lateral sclerosis (ALS) related mutations are clustered in FUS-NLS. We report here the structural, biochemical and cell biological characterization of the FUS-NLS and its clinical implications. The crystal structure of the FUS-NLS/Trn1 complex shows extensive contacts between the two proteins and a unique α-helical structure in the FUS-NLS. The binding affinity between Trn1 and FUS-NLS (wide-type and 12 ALS-associated mutants) was determined. As compared to the wide-type FUS-NLS (K(D) = 1.7 nM), each ALS-associated mutation caused a decreased …