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Protein Misfolding in Human Diseases

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Protein Misfolding in Human Diseases Linköping Studies in Science and Technology Dissertation No. 1239 Protein Misfolding in Human Diseases Karin Almstedt Biochemistry Department of Physics, Chemistry and Biology Linköping University, SE-581 83 Linköping, Sweden Linköping 2009 The cover shows a Himalayan mountain range, symbolizing a protein folding landscape. During the course of the research underlying this thesis, Karin Almstedt was enrolled in Forum Scientium, a multidisciplinary doctoral program at Linköping University, Sweden. Copyright © 2009 Karin Almstedt ISBN: 978-91-7393-698-9 ISSN: 0345-7524 Printed in Sweden by LiU-Tryck Linköping 2009 Never Stop Exploring 83 ABSTRACT The studies in this thesis are focused on misfolded proteins involved in human disease. There are several well known diseases that are due to aberrant protein folding. These types of diseases can be divided into three main categories: 1. Loss-of-function diseases 2. Gain-of-toxic-function diseases 3. Infectious misfolding diseases Most loss-of-function diseases are caused by aberrant folding of important proteins. These proteins often misfold due to inherited mutations. The rare disease carbonic anhydrase II deficiency syndrome (CADS) can manifest in carriers of point mutations in the human carbonic anhydrase II (HCA II) gene. One mutation associated with CADS entails the His107Tyr (H107Y) substitution. We have demonstrated that the H107Y mutation is a remarkably destabilizing mutation influencing the folding behavior of HCA II. A mutational survey of position H107 and a neighboring conserved position E117 has been performed entailing the mutants H107A, H107F, H107N, E117A and the double mutants H107A/E117A and H107N/E117A. We have also shown that the binding of specific ligands can stabilize the disease causing mutant, and shift the folding equilibrium towards the native state, providing a starting point for small molecule drugs for CADS. The only known infectious misfolding diseases are the prion diseases. The human prion diseases Kuru, Gerstmann-Sträussler-Scheinker disease (GSS) and variant Creutzfeldt-Jakob are characterized by depositions of amyloid plaque from misfolded prion protein (HuPrP) in various regions of the brain depending on disease. Amyloidogenesis of HuPrP is hence strongly correlated with prion disease. Amyloid fibrillation and oligomer formation of PrP in in vitro studies have so far been performed under conditions where mild to harsh conditions of denaturants of various sorts have been included. In this work we show the unusual behavior of recombinant human prion protein during protein aggregation and fibrillation when performed under non-denaturing conditions close to physiological. We show that HuPrP amyloid fibrils are spun and woven from disordered aggregates. 83 POPULÄRVETENSKAPLIG SAMMANFATTNING I denna avhandling presenteras resultat från studier om hur proteiner som veckar sig på fel sätt kan orsaka sjukdom. Den bakomliggande orsaken till att proteiner veckar sig på fel sätt är ibland att olika mutationer i vår arvsmassa gör att en utav de aminosyror som bygger upp ett protein har blivit utbytt mot en annan aminosyra med andra egenskaper. När ett protein veckas fel och förlorar sin struktur förlorar det också sin funktion och på så sätt kan en viktig funktion i cellen sättas ur spel och orsaka sjukdom. Proteiner har mycket viktiga uppgifter i våra celler och hjälper oss t.ex. att ta upp syre, försvara oss mot bakterier och virus och att bryta ner slaggprodukter. Studierna som presenteras här visar att när proteinet humant karboanhydras II, som finns i många olika vävnader i kroppen och är viktigt i många olika processer, muteras och blir instabilt, kollapsar ihop till en icke fungerande, halvveckad proteinklump. Det har undersökts hur det kan komma sig att bytet av en enda aminosyra (av 259 som finns i proteinet) kan orsaka den här stora förändringen. Det har visat sig att det inte är en aminosyras direkta kontakter med sina grannar som är den viktigaste parametern, utan snarare är det stora interaktionsnätverk som är viktiga när det gäller hur ett protein stabiliseras. Det har även undersökts hur prionproteinet (som är det protein som bl. a. orsakar Creutzfeldt-Jakobs sjukdom) kan byta struktur från en korkskruvsliknande och funktionell form till en silkestrådsliknande form som klumpar ihop sig och kan bilda plack i hjärnan. Studierna visar att det först bildas bollar av ihopklumpade prionproteiner som sedan vävs ut till tunna fibrer. 83 INCLUDED PAPERS This thesis is based on work presented in the following papers, which are listed below and included in the end of the thesis. Paper I Almstedt K., Lundqvist M., Carlsson J., Karlsson M., Persson B., Johnsson B-H., Carlsson U and Hammarström P. Unfolding a folding disease: Folding, misfolding and aggregation of the marble brain syndrome-associated mutant H107Y of human carbonic anhydrase II. (2004) J. Mol. Biol. 342, 619-633. Paper II Almstedt K., Mårtensson L-G., Carlsson U. and Hammarström P. Thermodynamic interrogation of a folding disease. Mutant mapping of position 107 in human carbonic anhydrase II linked to marble brain disease. (2008) Biochemistry. 47, 1288-1298. Paper III Almstedt K., Rafstedt T., Supuran C.T., Carlsson U. and Hammarström P. Small- molecule suppression of misfolding of mutated human carbonic anhydrase II linked to marble brain disease. In manuscript. Paper IV Almstedt K., Nyström S., Nilsson K. P. and Hammarström P. Amyloid Fibrils of Human Prion Protein are Spun and Woven from Disordered Aggregates. In manuscript. LIST OF ABBREVIATIONS ALS Amyotrophic lateral sclerosis ANS 8-anilino-1-naphtalenesulfonic acid BSE Bovine spongiform encephalopathy BTB Bromthymol blue CA Carbonic anhydrase CAA Carbonic anhydrase activator CADS Carbonic anhydrase II deficiency syndrome CAI Carbonic anhydrase inhibitor CD Circular dichroism CFTR Cystic fibrosis transmembrane conductance regulator CJD Creutzfeldt-Jakob disease DNA Deoxyribonucleic acid FFI Fatal Familial Insomnia GPI anchor Glycosylphosphatidylinositol anchor GSS Gerstmann-Sträussler-Scheinker Syndrome GuHCl Guanidine hydrochloride HCA II Human carbonic anhydrase II (wild type) HCA IIH107Y HCA IIpwt with a H107Y mutation HCA IIpwt Pseudo wild-type of HCA II with a C206S mutation HuPrP90-231 Human prion protein sequence 90-231 His HuPrP90-231 Human prion protein sequence 90-231 with an N-terminal hexa histidine tag His HuPrP121-231 Human prion protein sequence 121-231 with an N-terminal hexa histidine tag IAPP Islet amyloid polypeptide ICT Internal charge transfer NMR Nuclear magnetic resonance PRNP Gene encoding the prion protein PrPC Cellular form of prion protein PrPSc Disease associated scrapie form of prion protein Q0 Fraction of native contacts Rg Radius of gyration RTA Renal tubular acidosis TEM Transmission electron microscopy ThT Thioflavin T TICT Twisted internal charge transfer TSE Transmissible spongiform encephalopathy 83 TABLE OF CONTENTS INTRODUCTION ............................................................................................................ 5 PROTEIN STRUCTURE .................................................................................................. 9 α-helix .......................................................................................................................... 10 β-sheet .......................................................................................................................... 11 PROTEIN FOLDING AND MISFOLDING ................................................................ 12 Protein folding models .............................................................................................. 13 Protein aggregation ................................................................................................... 16 Amyloid fibrils ........................................................................................................... 17 THE MODEL PROTEINS ............................................................................................. 23 Carbonic Anhydrase .................................................................................................. 23 Human carbonic anhydrase II .............................................................................. 23 Inhibition and Activation of Carbonic Anhydrase ........................................... 26 Human Prion Protein ................................................................................................ 28 PROTEIN MISFOLDING DISEASES .......................................................................... 33 Carbonic Anhydrase II Deficiency Syndrome ....................................................... 35 Transmissible Spongiform Encephalopathy .......................................................... 38 Sporadic CJD ........................................................................................................... 39 Variant CJD ............................................................................................................. 39 Inherited prion disease .......................................................................................... 41 Iatrogenic CJD ........................................................................................................ 43 METHODS ...................................................................................................................... 45 Site Directed Mutagenesis ........................................................................................ 45 Enzyme Activity ........................................................................................................
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