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Cover photo credit: Hoch, K., Volk, D.E Structures of Thymosin Proteins Vitamins and Hormones (2016) 102, pp 1–24 Academic Press is an imprint of Elsevier 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States 525 B Street, Suite 1800, San Diego, CA 92101-4495, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom 125 London Wall, London, EC2Y 5AS, United Kingdom First edition 2016 Copyright © 2016 Elsevier Inc All rights reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein) Notices Knowledge and best practice in this field are constantly changing As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein ISBN: 978-0-12-804818-4 ISSN: 0083-6729 For information on all Academic Press publications visit our website at Publisher: Zoe Kruze Acquisition Editor: Alex White Editorial Project Manager: Helene Kabes Production Project Manager: Vignesh Tamil Cover Designer: Greg Harris Typeset by SPi Global, India Former Editors ROBERT S HARRIS KENNETH V THIMANN Newton, Massachusetts University of California Santa Cruz, California JOHN A LORRAINE University of Edinburgh Edinburgh, Scotland PAUL L MUNSON University of North Carolina Chapel Hill, North Carolina JOHN GLOVER University of Liverpool Liverpool, England GERALD D AURBACH Metabolic Diseases Branch National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Bethesda, Maryland IRA G WOOL University of Chicago Chicago, Illinois EGON DICZFALUSY Karolinska Sjukhuset Stockholm, Sweden ROBERT OLSEN School of Medicine State University of New York at Stony Brook Stony Brook, New York DONALD B MCCORMICK Department of Biochemistry Emory University School of Medicine, Atlanta, Georgia CONTRIBUTORS G Covelo Facultad de Biologı´a, Universidade de Santiago de Compostela, Santiago de Compostela, Spain C Dı´az-Jullien Facultad de Biologı´a, Universidade de Santiago de Compostela, Santiago de Compostela, Spain M Freire Facultad de Biologı´a, Universidade de Santiago de Compostela, Santiago de Compostela, Spain E Garaci University of Rome “Tor Vergata”; San Raffaele Pisana Scientific Institute for Research, Hospitalization and Health Care, Rome, Italy K Hoch Texas Children’s Microbiome Center, TCH Pathology, Houston, TX, United States K Ioannou Faculty of Biology, National and Kapodistrian University of Athens, Panepistimiopolis, Athens, Greece; King’s College London, Rayne Institute, London, United Kingdom Y Jung Pusan National University, Pusan, Republic of Korea J Kim Pusan National University, Pusan, Republic of Korea R King SciClone Pharmaceuticals, Inc., Foster City, CA, United States H.K Kleinman George Washington University, Washington, DC; NIDCR/NIH, Bethesda, MD, United States A Kumar Nanomedicine Research Laboratory, University of Delaware, Newark, DE, United States W Mandaliti University of Rome “Tor Vergata”, Rome, Italy E.D Marks Nanomedicine Research Laboratory, University of Delaware, Newark, DE, United States R Nepravishta University of Rome “Tor Vergata”, Rome, Italy; Faculty of Pharmacy Catholic University “Our Lady of Good Counsel”, Tirane, Albania xi xii Contributors G Ousler Kresge Eye Institute, Wayne State University School of Medicine, Detroit, MI; ORA Inc., Andover, MA, United States M Paci University of Rome “Tor Vergata”, Rome, Italy F Pica University of Rome “Tor Vergata”, Rome, Italy G.T Pipes Cardiovascular Drug Discovery, Discovery Biology Research & Development, Bristol-Myers Squibb, Pennington, NJ, United States L Renault Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ Paris-Sud, Universite Paris-Saclay, Gif-sur-Yvette, France D Rimmer Kresge Eye Institute, Wayne State University School of Medicine, Detroit, MI; ORA Inc., Andover, MA, United States R.C Robinson Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Biopolis; Yong Loo Lin School of Medicine, National University of Singapore; NTU Institute of Structural Biology; School of Biological Sciences, Nanyang Technological University; Lee Kong Chan School of Medicine, Singapore P Samara Faculty of Biology, National and Kapodistrian University of Athens, Panepistimiopolis, Athens, Greece C.S Sarandeses Facultad de Biologı´a, Universidade de Santiago de Compostela, Santiago de Compostela, Spain G Sosne Kresge Eye Institute, Wayne State University School of Medicine, Detroit, MI, United States O.E Tsitsilonis Faculty of Biology, National and Kapodistrian University of Athens, Panepistimiopolis, Athens, Greece C Tuthill SciClone Pharmaceuticals, Inc., Foster City, CA, United States P.S Vallebona University of Rome “Tor Vergata”, Rome, Italy D.E Volk Center for Proteomics and Systems Biology, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases; Department of Nanomedicine and Biomedical Engineering, The University of Texas Health Science Center at Houston, Houston, TX, United States Contributors xiii B Xue Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore J Yang Cardiovascular Drug Discovery, Discovery Biology Research & Development, Bristol-Myers Squibb, Pennington, NJ, United States PREFACE Thymosin peptides originally were isolated from the thymus gland and were found to stimulate the development of T cells; consequently, they were initially considered to be thymic hormones Later research revealed several related peptides and thymosins were found in many tissues In humans, there exist three families of beta thymosins, beta4, beta10, and beta15; of these, beta4 has been most studied Beta4 and beta15 families each are encoded by two separate genes and beta10 is encoded by a single gene There appears to be a single human gene responsible for the prothymosin alpha gene family (generating thymosin alpha 1), deriving from the thymus gland There are monomeric and polymeric beta thymosins The beta thymosins are involved in actin assembly, cytoskeletal remodeling, cell regulation, the cardiovascular system, and dermal healing; in addition, they have therapeutic effects on diseases of the ocular surface Alpha thymosin appears to have modulatory functions in the immune system This volume concentrates on the structure and functions of thymosins and their activities Also reviewed are the biological and clinical conditions in which thymosins are active and potentially therapeutic Initially, there is concentration on structure and biological function The second part of the book describes biological and clinical conditions involving the thymosins To begin, K Hoch and D.E Volk describe “Structures of thymosin proteins.” Chapter by L Renault reports on “Intrinsic, functional, and structural properties of β-thymosins and β-thymosin/WH2 domains in the regulation and coordination of actin self-assembly dynamics and cytoskeletal remodeling.” B Xue and R.C Robinson further review “Actininduced structure in the beta-thymosin family of intrinsically disordered proteins.” Then, M Freire, C.S Sarandeses, G Covelo, and C Dı´az-Jullien focus on “Phosphorylation of prothymosin α An approach to its biological significance.” Following, R Nepravishta, W Mandaliti, P.S Vallebona, F Pica, E Garaci, and M Paci report on the “Mechanism of action of thymosinα1: Does it interact with membrane by recognition of exposed phosphatidylserine on cell surface? A structural approach.” In Chapter 6, J Kim and Y Jung discuss “Thymosin beta as a potential regulator of hepatic stellate cells.” xv xvi Preface With respect to the role of thymosin alpha on the immune system, R King and C Tuthill author “Immune modulation with thymosin alpha treatment” and then P Samaria, K Ioannou, and C.E Tsitsilonis review “Prothymosin alpha and immune responses: Are we close to potential clinical applications?” The remainder of the volume concentrates on thymosin beta “Cardioprotection by thymosin beta 4” is described by G.T Pipes and J Yang E.D Marks and A Kumar report on “Thymosin β4: Roles in development, repair, and engineering of the cardiovascular system.” H.K Kleinman and G Sosne describe “Thymosin β4 promotes dermal healing.” The concluding chapter is “Thymosin beta 4: A potential novel therapy for neurotrophic keratotherapy, dry eye, and ocular surface diseases” by G Sosne, D Rimmer, H.K Kleinman, and G Ousler The illustration on the cover is Fig 7, reproduced from Chapter 1:“Structures of thymosin proteins” by K Hoch and D.E Volk The legend is: Crystal structure of alpha actin bound to gelsolin–thymosin beta-4 C-terminal helix chimera The helix is the minus-end capping helix and it competes with DNAse I binding at this site Atomic coordinates were obtained from the Protein Data Bank (PDB ID 1T44; Irobi et al., 2004) As usual, Helene Kabes of Elsevier, Oxford, UK, played a major role in the development of the published work in tandem with the Reed Elsevier group in Chennai, India GERALD LITWACK Toluca Lake, North Hollywood, CA April 2, 2016 CHAPTER ONE Structures of Thymosin Proteins K Hoch*, D.E Volk†,{,1 *Texas Children’s Microbiome Center, TCH Pathology, Houston, TX, United States † Center for Proteomics and Systems Biology, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, The University of Texas Health Science Center at Houston, Houston, TX, United States { Department of Nanomedicine and Biomedical Engineering, The University of Texas Health Science Center at Houston, Houston, TX, United States Corresponding author: e-mail address: Contents Introduction Structures of Prothymosin α and Parathymosin 2.1 Native Structure of Prothymosin α 2.2 pH-Induced Structures of Prothymosin α 2.3 Structure of the Prothymosin α Carboxy-Terminal Peptide 2.4 Structure of Prothymosin α in a Complex with the Keap1 Kelch Domain 2.5 Structure of Prothymosin α in the Presence of Zn2 + 2.6 Structure of Parathymosin α Structures of Tα1 3.1 Structure of Tα1 in Water 3.2 Structure of Tα1 in Mixed Solvents 3.3 Structure of Tα1 in Membrane-Like Environments Structures of Beta Thymosin Proteins 4.1 Structure of Thymosin β9 4.2 Structure of Human Thymosin β10 4.3 Structure of Thymosin β4 4.4 Solution Phase Structure of Thymosin β4 Interacting with Actin 4.5 Crystallographic Structures of Thymosin β4 Chimeras Interacting with Actin Conclusions Acknowledgments References 2 4 7 9 10 12 14 14 15 16 16 17 20 20 20 Abstract The thymosin proteins are all short, highly charged, intrinsically unstructured proteins under natural conditions However, structure can be induced in many of the thymosin proteins by providing charge neutralization at low pH or by the addition of Zn2+ ions, organic reagents such as trifluoroethanol, hexafluoropropanol, or n-dodecyltrimethylammonium bromide, or interactions with their natural binding partner proteins The differing structures of thymosin alpha and thymosin beta proteins have been studied by circular dichroism, nuclear magnetic resonance, and crystallographic methods in order to better understand Vitamins and Hormones, Volume 102 ISSN 0083-6729 # 2016 Elsevier Inc All rights reserved K Hoch and D.E Volk the role of these proteins In this structural biology review the structures of prothymosin, parathymosin, thymosin alpha-1, and several beta thymosin proteins, in both native states and under secondary structure-inducing conditions are discussed INTRODUCTION Although the thymosin proteins were originally discovered from fractionations of calf thymus tissue, and thus so named, they are genetically unrelated while being distributed widely throughout most tissues and play important, yet very different, roles in cells They are highly charged proteins with no or few aromatic amino acids and thus lack stable tertiary structure unless induced by interactions with partnering proteins or unnatural solvent conditions The active peptides are typically short The beta thymosins are each about 43 amino acids long, while thymosin α1 (Tα1) is only 28 amino acids long, although its precursor, prothymosin, is nearly 100 bases long Tα1 and prothymosin α have been used to treat a variety of viral infections, including HIV (Mosoian et al., 2006, 2010), chronic hepatitis B (Iino et al., 2005; You et al., 2006), chronic hepatitis C (Andreone et al., 2001; Kullavanuaya et al., 2001), cytomegalovirus (Bozza et al., 2007), and invasive aspergillosis (Segal & Walsh, 2006), due to their immunological effects (Markova et al., 2003; Romani et al., 2006) The thymosin beta proteins are major sequestering agents of monomeric actin protein, thus allowing cells to have a high concentration of G-actin at the ready for quick use As such, these proteins are clinically important The structures of the thymosin proteins are explored under a variety of conditions in this review STRUCTURES OF PROTHYMOSIN α AND PARATHYMOSIN 2.1 Native Structure of Prothymosin α Prothymosin α (ProTα), a 110-amino acid protein first discovered by Haritos, Tsolas, and Horecker (1984), has a very unusual amino acid sequence containing no aromatic (Tyr, Trp, Phe, His) or sulfur-containing residues (Met, Cys), while being very acidic, containing 35 glutamates and 19 aspartates (Goodall, Dominguez, & Horecker, 1986) As the name suggests, prothymosin α is a precursor to the 28 amino acid protein Tα1 discovered by Goldstein et al (1977) Using traditional biophysical methods, such as X-ray scattering, dynamic light scattering, CD, NMR, mass spectrometry, and gel-filtration, early studies showed that ProTα has a random coil Thymosin Protein Structures structure at physiological pH (Cordero, Sarandeses, Lopez, & Nogueira, 1992; Gast et al., 1995; Watts, Cary, Sautiera, & Crane-Robinson, 1990) 2.2 pH-Induced Structures of Prothymosin α Structure can be induced in ProTα by a number of methods (Table 1) First, it was shown by CD and NMR that lowering the pH induced a small amount of structure to prothymosin (Watts et al., 1990) Later it was shown that the presence of about 50% trifluoroethanol (TFE) at pH 2.4 induced approximately 69% helical structure in ProTα, as measured by CD spectra (Gast et al., 1995), but significantly less helical structure was observed without TFE: $0% at pH 7.4, 8% at pH 4.6, and 13% at pH 2.4 The presence of no secondary structure at neutral pH and a little secondary structure at low pH was first observed by NMR and CD (Watts et al., 1990) Subsequently, it was shown that low pH alone was enough to cause a partially folded collapsed structure, presumably due to neutralization of the acidic residues (Uversky et al., 1999) Interestingly, far-UV CD data suggested no structural changes occur between pH 5.5 and 9.5, but that a dynamic, partially collapsed structure(s) forms between pH 3.5 and 5.5 This structure was described as a compact denatured structure, and no long-range NOE signals were detected in NMR spectra At neutral pH, ProTα could have a charge as large as À44 based on its primary amino acid sequence Therefore, neutralization of this acidic protein at low pH can lead to structural collapse near the amino acid neutralization sites Secondary structure was also induced by changes in temperature and the addition of n-dodecyltrimethylammonium bromide (Pomco et al., 2001) Table Helical Structure of Prothymosin α as a Function of pH pH TFE Helical Content (%) 2.4 Yes 69a 2.0 No 20b 2.4 No 13a 2.5 No $15c 4.6 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recovery after thymosin beta4 treatment in mice with experimental auto encephalomyelitis Neuroscience, 164(4), 1887–1893 10.1016/j.neuroscience.2009.09.054 Zoukhri, D., Hodges, R R., Byon, D., & Kublin, C L (2002) Role of proinflammatory cytokines in the impaired lacrimation associated with autoimmune xerophthalmia Investigative Ophthalmology & Visual Science, 43(5), 1429–1436 INDEX Note: Page numbers followed by “f ” indicate figures, and “t” indicate tables A ABPs See Actin-binding proteins (ABPs) ACE See Angiotensin converting enzyme (ACE) Acidic protein neutralization, Actin, 27–28, 37 Actin-binding proteins (ABPs), 27–28, 33, 39, 41–43 Actin cytoskeleton, 27–28 Actin filaments (F-actin), 27–28, 36–37 Actin interaction, 60–61, 63 Actin interface analysis, Tβ4 EST data, 65 hydrophobic interactions, 64, 65f identical interface residues, 66 isoforms, sequence alignment of, 66, 67f nonidentical interface residues, 66–68 Pichia isoforms, 66 PISA, 64, 67f Active thymic fraction, 242 Acute infections, 159–162 Acute ischemia, 232–233 Akt-dependent mechanism, 188 See also Miscellaneous functions, proTα Akt/PI3K pathways, 235–236 Alarmins, 195 Allogeneic cell-mediated lympholysis, 185–186 α-thymosins, 74, 102 origin of, 74–76 precursor of, 74–77 Amide protons, 60 Amniotic membrane transplantation (AMT), 284–285 Angiogenesis, 211, 219, 221, 253, 258–259 Angiotensin converting enzyme (ACE), 137–138, 260–262 Ankyrin repeat protein, 287–288 Anoxic brain tissue, 234–235 Antiapoptotic activity, 257–258 Antifibrotic activity, 260–262 Antiinflammatory, 257–258, 260–262 Antiparallel β-pleated sheet, 4, 4f Apoptosis, 4, 187–188, 192 Arterial blockages, 232 Attenuated total reflectance Fouriertransform infrared (ATF FT-IR), B Bandage lenses, 297 β-Thymosins (βT), 26–27 expression as repeats and in modular proteins, 32 as small proteins of kDa, 28–32, 29f as genuine G-actin sequestering proteins, 37–39 sequences of, 28–34, 29f WH2 domains, 27–28 in actin assembly, 40–44 functional versatility, 40–44 sequences of, 28–34, 29–30f βT repeat, 56–57 β-turn spanning residues, 4–5 Beta-thymosins (βTs), intrinsically disordered proteins in complex with actin NMR-based Tβ4, 59f, 60 X-ray structures, 60–64 in solution, 57–60 Tβ4, actin interface analysis, 64–68 Bile duct-ligated (BDL), 132–135 Biologic response modifiers (BRMs), 180, 185–186 Biophysical methods, 2–3 Blepharitis, 297 BRMs See Biologic response modifiers (BRMs) C Cancer, 180–181, 185–186 animal models, 156–158 non-small cell lung, 166 quality of life in, 166–167 307 308 Cardiac system, development of in fetal development amino acid structure, 230–231 β–thymosins, 230–231 interfering RNA strategy, 231 MMP, 230–231 Tβ4, 231 urothelial carcinomas, 231–232 general timeline cardiac anlage, 229 completion of, 229–230 fetal heart, 230 genetic and morphological malformations, 230 high-resolution imaging, 229 pericardial cavity, 229 postnatal treatment options, 230 Cardiomyocytes, 188, 233 Cardioprotection cell and tissue effects to, 213–216 in preclinical animal models, 217–220 Cardiovascular disease, 232 Cell migration, 279–281 Charge–charge interactions, Chemical cross-linking data, 60 Chronic dry eye disease, 293 Chronic infections, 162–163 Ciboulot residue, 62 Circular dichroism, 57–58 See also Thymosin β4 (Tβ4) Collagen, 232–233 Colorectal cancer, 139–140, 157 Controlled adverse environment (CAE™), 294–295 Cornea, 282 Corneal reepithelialization, 296–297 Cortical neurons, 187–188 Costimulatory molecules, 194 CREB-binding protein (CBP), 192 Crystal packing, 61 C-terminal helix , Tα1, 11–12, 11f CTLs See Cytotoxic T lymphocytes (CTLs) Cyclosporin A (CSA), 293–294 Cytotoxic T lymphocytes (CTLs), 184–186 D Damage-associated molecular pattern molecules (DAMPs), 195, 199 Index DCs See Dendritic cells (DCs) Decapeptide proTα(100–109), 191, 197–199 Dendritic cells (DCs), 153–154, 186 Dermal burn, thymosin beta activity, 259–260 Dermal healing study, thymosin beta 4, 253–255, 253–254t inflammation, 256–257, 256f proliferation, 257 remodeling, 257 Dermal wound repair, thymosin beta in, 268–269 Dimyristoylphosphatidic acid (DMPA), 12–13 Dimyristoylphosphatidylcholine (DMPC), 12–13 DNA remodeling, 192 DNase I loop, 60–61 Drug-eluting patches, 234f Dry eye syndrome (DES) androgens, 292–293 clinical diagnosis of, 292–293 cyclosporin ophthalmic emulsion, 293–294 endocrineimmunological systems, 292–293 human tear film, 292–293 hyperosmolar stress, 293 IL-1, 293 NF-kB signaling, 293 Tβ4, clinical efficacy of, 294–295 Dry Eye Workshop (DEWS), 292–293 E E-cadherin, 139–140 ECM See Extracellular matrix (ECM) Electron density, 63 Elizondo-Riojas study, 10–11 Endothelial nitric oxide synthase (eNOS), 240 Endothelial progenitor cells (EPCs), 214–215 End-stage renal disease (ESRD), 168–169 Enzymatic immunoassay, 128–129 EPCs See Endothelial progenitor cells (EPCs) Epidermal growth factor (EGF), 285 Epidermolysis bullosa wounds, 266–267 309 Index ESRD See End-stage renal disease (ESRD) Evidence, proTα alarmin, act as DAMPs, 195 HMGB1, 195–196, 196t PAMPs, 195 thymosins, 195–196 extracellular role of affinity cross-linking, 194–195 chromatography, 194–195 costimulatory molecules, 194 cytokine-like activities, 194–195 IL-2 receptor, 194 in vivo studies, animals, 194 intracellular role of apoptotic stimuli, 193f histone H1, 192, 193f implication in, 192 myeloma cells proliferation, 192 Extracellular matrix (ECM), 122, 124–126, 137–138, 232–233 Extracellular receptor-mediated Tβ4, 213 G-actin, 27–32, 36–37, 40–41, 45–46f ADP, 39 ATP, 44–46 fuzzy complex, 44–48 sequestering proteins, 37–39 G-actin-sequestering peptide, 122–123 Gelsolin (G1), 17, 18f, 60–61 Gene transcription, 192, 197–199 Glial fibrillary acidic protein (GFAP), 124–126 Glutathione (GSH), 154 Hepatic fibrosis, 124 Hepatic stellate cells (HSC) autocrine/paracrine signaling, 124–126 damaged livers, 132–135, 135f ECM proteins, 124–126 fibrogenic cell, 124–126 fibrous matrix production, 140–141 GFAP, 124–126 inactivation of, 135–136, 136f LX-2 cells, 135–136 persistent activation of, 126 PI3K/AKT pathway, 124–126 quiescent, 132–135 Tβ4, activation, 134f, 135–136 transdifferentiation of, 130–132 Hepatitis C virus (HCV), 129–130 Hepatoblastoma, 139–140 Hepatocellular carcinoma (HCC), 165–166 Hepatocyte growth factor (HGF), 130–132 Hepatocytes, 123–124 Heteronuclear single quantum coherence(1H,15N-HSQC), 1,1,1,3,3,3-Hexafluoropropanol (HFP), 14, 15f High-mobility group protein B1 (HMGB1), 195–196 High proTα levels, 192–194 Hormones peptidic, 114–115 thymic, 113 HSC See Hepatic stellate cells (HSC) Human dermal healing, 254–255 Human immunodeficiency virus (HIV)-1, 186–187 Human neutrophils, 190–191 Human thymosin β10, 15–16, 15t Human umbilical vein endothelial cells (HUVECs), 281 Hybrid protein, 60–63 Hydrogen bonding interactions, Hyperproliferative cells, 197–199 Hypoxia, 257–258 H I HCC See Hepatocellular carcinoma (HCC) Healed state, 232–233 Healthy livers, 132–135, 134f IDPs See Intrinsically disordered proteins (IDPs) IDRs See Intrinsically disordered regions (IDRs) F F-actin See Actin filaments (F-actin) Far-UV CD data, Fibrotic disease, 122–123 Fructose 1,6-bisphosphate (FBP), 90 Fuzzy complex, G-actin, 44–48 G 310 ILK See Integrin-linked kinase (ILK) Immune modulation, 163 Immune suppression, thymosins α1 in, 155–159 Immunofluorescent (IF) staining, 132–135, 133f Immunohistochemical (IHC) staining, 129–130, 129f Immunostimulatory activity, ProTαderived peptides amino-terminal peptide Tα1, 190 carboxy-terminal, 190–191 diverse activities, 188–189, 189t immune-based assays, 188–189, 189t middle segment peptides, 191–192 Infectious disease acute infections study, 159–162 animal models of, 155–156 chronic infections study, 162–163 Insulin-like growth factor (IGF-1), 285 Insulin resistance, 188 Integrin-linked kinase (ILK), 39, 212, 239–240 Interferon (IFN)-γ, 185–186 Intrinsically disordered proteins (IDPs), 34, 57 function, 35–37 intrinsic and protein–protein interaction properties, 34–35 Intrinsically disordered regions (IDRs), 34 function, 35–37 intrinsic and protein–protein interaction properties, 34–35 Intrinsically unstructured proteins (IUPs), 57 Intrinsic and protein–protein interaction property, 34–35 Ischemic stroke, 233 J Junction-mediating and regulatory protein (JMY), 41–42 K Keap1 Kelch domain, 4–7, 6f Kelch-binding domains, 4–5 keratinization, 297 Kupffer cells, 129–130, 129f Index L Laminin-332 (LM-332), 282 See also Wound healing, Tβ4 Left anterior descending (LAD) artery, 234f Liver disease, 124 fibrosis, 128, 140–141 sinusoids, 123–124 LKKT motif, 59, 61 LX-2 cells, 132–135, 133f M MAL See Myocardin-related transcription factor A (MRTF-A) Matrix metalloproteinase (MMP), 230–231 Melanoma, 163–165, 164f Membrane-like environments, DMPA, 12–13 Mesenchymal stem cells (MSCs), 235–236, 241 Methyl-CpG-binding protein (MeCP2), 130–132 MHC class II expression, 197–199 MI See Myocardial infarction (MI) Micellar environment, structural study, 104–105 MicroRNA (miRNAs), 298 Miscellaneous functions, proTα, 188 Mixed lymphocyte reactions (MLRs), 181–182 Molecular recognition elements (MoREs), 34–35 Molecular recognition features (MoRFs), 34–35 Monomeric actin, 16–17 Monomeric/globular actin (G-actin), 27–28 MoREs See Molecular recognition elements (MoREs) MoRFs See Molecular recognition features (MoRFs) M2 protein, 90, 92 MRTF-A See Myocardin-related transcription factor A (MRTF-A) MSCs See Mesenchymal stem cells (MSCs) Multifaceted immune activity, ProTα anticancer animal studies, 185–186 311 Index CD4+ T cells, 186 CTLs, 186 immunoenhancing effect, 184–185 MHC class II expression, 184–185 monocytes, 185–186 NK cell markers, 185–186 PBMCs, 186 proteomics, 186 antiviral, 186–187 miscellaneous functions, 188 neuroprotective functions, 187–188 Multimodular proteins, WH2 domain in, 32–33 Myocardial infarction (MI), 210, 215–218, 217t, 233 Myocardin-related transcription factor A (MRTF-A), 211–212 N National Institutes of Health Stroke Scale, 233–234 Natural killer (NK) cells, 154 NC37 cells, 86–88, 88f lysates of, 91f PK activity, 87–88, 89f ProTα activity, 87–88, 88–89f Necrosis, 197–199, 198f Necrotic neurons, 183–184 Neuroparalytic keratitis See Neurotrophic keratopathy (NK) Neuroprogenitor cells (NPCs), 298–299 Neuroprotective functions, proTα, 187–188 Neurotrophic keratopathy (NK) degenerative corneal disease, 283 neuroanatomic mechanism, 283–284 ocular surface, 283–284 treatment for AMT, 284–285 cord blood, 285 corneal damage, 284 NGF, 285–286 placebocontrolled studies, 285 platelet-rich fibrin tears, 285 trigeminal nerve, 283–284 NF-kB activation, 282–283 Nitrogen resonances, 60 NLS See Nuclear localization signal (NLS) NMR structural study micellar environment, 104–105 15 N NMR spectroscopy study of interaction thymosins α1, 111–113 trifluoroethanol solution, 104 NOE signal See Nuclear Overhauser enhancement (NOE) signal Nonparenchymal cells (NPCs), 123–124 Nonprogressive cerebral infarction (NP), 233–234 Non-small cell lung cancer (NSCLC), 166 NPFs See Nucleation-promoting factors (NPFs) NSCLC See Non-small cell lung cancer (NSCLC) Nuclear factor-kappa B (NF-kB), 188 Nuclear localization signal (NLS), 4, 4f, 41–42, 74–76, 183–184 Nuclear magnetic resonance (NMR), 2–3, 7, 56–58 Nuclear magnetic spin-lattice relaxation, 107–108 Nuclear Overhauser enhancement (NOE) signal, 10–11, 16, 57–58 Nucleation-promoting factors (NPFs), 32–33 O Oligoprogenitor cells (OPCs), 298–299 Oxidative stress, 192, 197–199 P PAMPs See Pathogenassociated molecular patterns (PAMPs) Parathymosin α, structure of primary structures of, 7–8, 8t vs prothymosin α, 8, 9t Parenchymal cells, 123–124 Pathogenassociated molecular patterns (PAMPs), 195, 199 PDGF-ββ–dependent proliferation, 130–132 PDGF-β receptor, 130–132 Peptidic hormones, 114–115 Pharmacokinetics (PK), 295–296 Phosphatidylinositol 3-kinase (PI3K), 240 Phosphatidylserine, thymosins interaction, 110, 110f 312 Phospholipidic membrane interactions, 106 Phosphorylation of prothymosin-α, 79–92 biological significance, 92–94 in proliferating cells, 82–92, 83–84f, 88–89f in vitro vs in vivo, 79–82 PKC See Protein kinase C (PKC) Plasmin, 138–139 Platelet-derived growth factor (PDGF), 124–126 Polycaprolactone (PCL), 238–239 Polymorphonuclear leukocytes (PMNs), 279–280 Posttranslational modifications (PTMs), 35–36, 41 Potent adjuvant, hepatitis B virus, 186–187 Pressure ulcer, 265–266 Primary immune deficiency, 159 Profibrogenic markers, 135–136 Profilin, 38–39 Profilin–thymosin β4, 17 Proliferating cells, ProTα phosphorylation, 82–92, 83–84f, 88–89f Proline, 62–63 Prolyl oligopeptidase (POP), 137–138, 138f Prostaglandin E2 (PGE2), 185–186 ProTα (100–109), 190–191, 197–199, 198f Protein kinase C (PKC), 103 Proteins G-actin sequestering, 37–39 multimodular, WH2 domain in, 32–33 Proteomic analysis, 186–187 Prothymosin α (ProTα), 74–76, 81f biological function of, 78–79 cytoplasmic kinase characterization, 87–92 gene expression, 78 immune responses action, mechanism of, 197–199 alarmin, act as, 195–196 extracellular role of, 194–195 immunostimulatory activity, 188–192 intracellular role of, 192–194 isolation and properties, 181–184 multifaceted immune activities of, 184–188 phosphorylation, 79–82 Index biological significance, 92–94 in proliferating cells, 82–92, 83–84f, 88–89f primary structure of, 75f, 76 proteolysis of, 77 purification of, 80 purified characterization, 82–87, 89f role, 78–79 structure of carboxy-terminal peptide, Keap1 Kelch domain, 4–7, 6f native structure of, 2–3 pH-induced, 3, 3t Zn 2+, presence of, subcellular distribution of, 77 PTMs See Posttranslational modifications (PTMs) p53 transcription factor, 298–299 Purinergic receptors, 281 Q Quality of life (QOL), 166–167 R Rankin Scale, 233–234 Reactive oxygen species (ROS), 124–126 Regeneration, tissue, 255, 257–258, 258f, 264–265 Remodeling phase, 232–233 Reverse transcription polymerase chain reaction (RT-PCR), 130–132 Robust CTL responses, 186–187 S Schirmer’s test, 292–293 SDS See Sodium dodecylsulfate (SDS) Selective labeling, Tβ4, 60 Sepsis, 160, 161f Sequence alignment, 62–63 Short linear peptide motifs (SLiMs), 36–37 Sodium dodecylsulfate (SDS), 12–13, 104–106 Spanning middle segment sequences, 191 Stem cells, 255, 258–259 Stimulated innate immunity cells, 197–199 Stroke, 233 Index T TACE See Transcatheter arterial chemoembolization (TACE) Tandem thymosin β4 structure, 18–20, 19f Tβ4 See Thymosin β4 (Tβ4) 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), 236 TF5 See Thymosin fraction V (TFV) TFE See Trifluoroethanol (TFE) TGF–β See Transforming growth factor-β (TGF–β) T helper cells, 154 Thymalfasin, 152 Thymic hormone, 113, 180, 183, 199 Thymosin β4 (Tβ4), 29–32, 210, 252 actin interface analysis, 64–68 activated cells, 215 active sites on activities in unknown sequences, 262–263 cell surface receptor ATP synthase, 263 peptide 1–4, 260–262 peptide 1–15, 262 peptide 17–23, 262 peptide 40–43 (AGES), 262 in animal models, dry eye, 294 antiinflammatory effects, 286–288 in aqueous solution, 58 beta-thymosins, 126–127 biological activities of, 278, 279f cardiac hypertrophy, 228 cardiac system, development of in fetal development, 230–232 general timeline, 229–230 cardioprotection by, 217–220 cell growth promotion, 263–264 clinical efficacy of in dry eye, 294–295 in wound healing, NK, 288–292 clinical safety evaluations of, 295–296 clinical study, 220–221 crystallographic structures of, 17–20 dermal healing study human, 254–255 inflammation, 256–257, 256f proliferation, 257 remodeling, 257 in dermal wound repair, 268–269 313 dosing regimens and impacts, 217t dry eye syndrome (DES), 292–294 ECM components, 127–128 effects of, 221 expression of, 126–128 G-actin sequestering peptide, 278 hepatic expression, 128–130 hepatic stellate cells (HSCs), 124–126 human dermal study epidermolysis bullosa wounds, 266–267 phase safety trial, 265 pressure ulcer, 265–266 venous stasis ulcer, 266 and inflammation, 282–283 in liver Ac-SDKP fragment, effects of, 137–138 cancers, 139–140 endogenous role, 132–136 exogenous role, 130–132 hepatic expression of, 128–130 signaling pathway in, 138–139 liver cells and diseases, 123–124 in mixed organic-aqueous solvent, 57–58 mutants, 59–60 neurotrophic keratopathy (NK), treatment for, 284–286 NMR-based, actin model, 60 polypeptides, 278 potency of, 214 potential indications for, 296–299 preclinical animal studies with, 264–265 progression and repair heart attack, pathogenesis of, 232–233 stroke and subsequent repair, 233–235 properties, 210–211 role, 210 safety, 267–268 sequence, 31f signaling pathways downstream of, 211–213 solution phase structure of, 16–17 tissue engineering cell differentiation, 239–241 direct injections, 235–236 scaffold coating, 237–239 transgenic, 214 314 Thymosin β4 (Tβ4) (Continued ) treatment, 126–127, 214–215 unpolymerized G-actin, 126–127 in wound healing, 279–282 X-ray structures, 60–64, 64f Thymosin β9, 14, 15f Thymosin β10 (Tβ10), mixed organic-aqueous solvent, 58, 59f Thymosin fraction V (TFV), 74–76, 102 dissecting immunopotentiating properties, 182–183 peptides, isoelectric point of, 182 radioimmunoassay, 183 Tα1, 182–183 immunoactive thymic extract immune responses, 181 In vitro, 181–182 In vivo, 181–182 MLRs, 181–182 thymus, 181 Thymosin proteins β4 crystallographic structures of, 17–20 solution phase structure of, 16–17 β9, 14 human thymosin β10, 15–16 parathymosin α, structure of, 7–8 prothymosin α (ProTα), structure of carboxy-terminal peptide, Keap1 Kelch domain, 4–7 pH-induced, Zn 2+, presence of, Tα1, structures of in membrane-like environments, 12–13 in mixed solvents, 10–12 in water, 9–10 Thymosins α1 (Tα1), 74–76, 102, 152 amino acid sequence of, 75f animal models cancer, 156–158 infectious disease, 155–156 vaccine response, 158 behavior of, 108–109 circular dichroism spectroscopy of, 108 clinical study acute infections, 159–162 Index cancer, 163–167 chronic infections, 162–163 hepatocellular carcinoma, 165–166 immune suppression, 158–159 melanoma, 163–165, 164f non-small cell lung cancer, 166 primary immune deficiency, 159 in vaccine enhancement, 167–169 immune-stimulating mechanism of action of, 152–155, 153f implications binding to membrane and cells, 114–115 binding to phosphatidylserine exposure, 113–114 interaction, 103 perdeuterated DPC and perdeuterated DPC–SDS micelles, 107–108 phosphatidylserine in membranes, 110, 110f in membrane-like environments, 12–13 DMPA, 12–13 DMPC, 12–13 negatively charged molecules, 12–13 NOEs, 13 N-terminal domain, 13, 14f mixed DPC-D38/SDS-D25 micelles, 106–107, 107f in mixed solvents C-terminal helix, 10–12 hydrophilic side, 11–12, 11f hydrophobic side, 11–12 NOE signals, 12 positive lysine residues, 12 molecular dynamics simulation of, 106–107 NMR-derived structures of, 10–11, 10f 15 N NMR spectroscopy study of interaction, 111–113 origin of, 77 structure, 105f univocal mechanism of action of, 103 upregulation, 103 in water, 9–10 Thymosins α11 (Tα11), 77 315 Index Tissue engineering cell differentiation, 239–241 cardiac fibroblasts, 241 eNOS, downstream activation of, 240 epithelial–mesenchymal transition effects, 239–240 intercellular β–catenin, 239–240 in vitro and in vivo, 241 MSCs, 241 nanoscaffolds, 241, 242f NF-kB pathway, 241 PI3K, 240 Tβ4, scaffolds, 240 direct injections, 235–236 cognitive function, 236 drug-eluting nanoscaffolds, 236, 237f endogenous upregulation of, 235–236 intracranial hemorrhaging, 236 in vivo, 236 MSCs, 235–236 neovascularization effect, 235–236 TCDD, 236 thymic mechanism, 235 scaffold coating, 237–239 angiogenesis, 238 collagen-driven remodeling, 238–239 micropatterned grooves, 238 PCL, 238–239 peptide release, 237–238 Radisic lab, 238 Tβ4 coatings, 238–239, 239f translational skin tissue, 237–238 Tissue inhibitor of metalloproteinase (TIMP)-1, 130–132 Tissue plasminogen activator (tPA), 234–235 Tissue regeneration, 255, 257–258, 258f, 264–265 TLR See Toll-like receptor (TLR) TLR agonists, 199 Toll-like receptor (TLR4), 186 Toll-like receptor (TLR), 103, 153 Transcatheter arterial chemoembolization (TACE), 165 Transforming growth factor-β (TGF–β), 124–126, 285 Trifluoroethanol (TFE), 3, 10–12, 104 Tryptic peptides, 79–80 Tumor necrosis factor (TNF)-α, 185–186 U Ulcer pressure, 265–266 venous stasis, 266 V Vaccine enhancement, thymosins α1, 167–169 Vaccine response, thymosins α1, 158 Vascular reperfusion, 234–235 Vehicle control, 294 Venous stasis ulcer, 266 Ventricular remodeling, 233 W WASP homology (WH2), 16–17 Western blot assay, 132–135, 133f WH2/β-thymosin domains, 27–28 IDRs, 44–48 repeats of, 42–43 sequences of, 28–34, 29–30f structure–function relationships, 47–48 Wiskott–Aldrich syndrome protein (WASP) homology domain 2, 32–33, 56–57 Wound healing, Tβ4 and antiinflammatory effects corneal healing, 286 membrane rafts, 287–288 pleiotropic molecule, 288 PMNs, 286 potent proinflammatory cytokines, 286 TNF-α, 287 TNFR1, translocation of, 287–288 ATP synthase, 281 extracellular matrix remodeling, 282 G-actin-binding protein, 281 HUVECs, 281 LM-332, 282 MMPs, 282 NK cell migration, 288 conventional herapies, 288–289 corneal epithelial defect, 288–289, 289f dramatic healing, 291 geographical defects, 290t neurotrophic corneal defects, 291–292 ocular surface inflammation, 291–292 316 Index ciboulot first βT repeat, N-terminal segment of, 61 second βT repeat, C-terminal segment of, 62 Tβ4 C-terminal segment of, 60–61 full-length and n-terminal segment of, 63–64 structure-based models, 62–63 Wound healing, Tβ4 (Continued ) punctate erosions, 289–291, 290t reepithelialization, 288 slit lamp appearance, 289–291 platelets, 279–280 pleiotropic effects, 281 purinergic signaling pathways, 281 stem cell migration and differentiation, 279–280 X X-ray crystallography, 56–57, 59f, 60–61 X-ray structures, beta-thymosins Z ZADAXIN®, 152 ... alpha and thymosin beta proteins have been studied by circular dichroism, nuclear magnetic resonance, and crystallographic methods in order to better understand Vitamins and Hormones, Volume 102. .. oxygen and the G45 amide proton, and between the E46 carbonyl oxygen and the N41 amide group Choy and coworkers investigated the structure of ProTα alone and in the complex formed between ProTα and. .. system This volume concentrates on the structure and functions of thymosins and their activities Also reviewed are the biological and clinical conditions in which thymosins are active and potentially
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