Heat Shock Proteins of Malaria (Advances in Experimental Medicine and Biology, 1340)

This new edition describes the role of heat shock proteins in the life cycle of malaria parasites, particularly in the context of intracellular parasite stages. Thoroughly revised, this work provides a general introduction to the structural and functional features of heat shock proteins with a special focus on their role as molecular chaperones in ensuring protein quality control. The emphasis is on the heat shock protein families from __Plasmodium falciparum__, and their role in proteostasis and the development of malaria pathology. Moreover, the authors explore the latest prospects of targeting heat shock proteins in antimalarial drug discovery either directly or in combination therapies. Readers will experience a functional analysis of the individual families of heat shock proteins and their cooperation in functional networks, including both the parasite-resident proteome and the exportome released into host cells during intracellular stages. Subcellular and extracellular organelles such as the apicoplast and the Maurer’s Clefts associated with __Plasmodium__ species are discussed in detail. The book highlights the role of heat shock proteins in the development and function of these structures. Biochemical expertise and the inclusion of novel therapeutic solutions make this collection a unique reference for experts in heat shock protein research, parasitology and infectious diseases, cell stress, molecular biology and drug discovery. Not least, advances in malaria control will contribute to ending epidemics and ensuring healthy lives in line with the UN Sustainable Development Goals. Preface 6 Acknowledgments 7 Contents 8 Editors and Contributors 10 Chapter 1: Introductory Chapter: The Importance of Heat Shock Proteins in Survival and Pathogenesis of the Malaria Parasite Pl... 13 1.1 Introduction 14 1.2 Parasites are Highly Dependent on HSPs 15 1.3 At Home: Cytosolic Plasmodium HSPs 15 1.4 Into the Wild: Plasmodium HSPs Involved in Interaction with the Host 17 1.5 Achilles ́ Molecular Heel: HSPs as a Target for Drug Development 19 1.6 Concluding Comments 19 References 20 Chapter 2: General Structural and Functional Features of Molecular Chaperones 22 2.1 Introduction to Molecular Chaperones and Stress at a Cellular Level 23 2.2 Classification of Heat Shock Proteins as Molecular Chaperones 24 2.3 Foldases: Molecular Chaperones Involved in Protein Folding 28 2.3.1 The Hsp60/Chaperonin Family of Molecular Chaperones 28 2.3.2 The Hsp90 Family of Molecular Chaperones 31 2.3.3 The Hsp70 and Hsp110 Family of Molecular Chaperones 40 2.3.4 The JDP Family of Molecular Chaperones 44 2.4 Holdases and Unfoldases: Molecular Chaperones Preventing Protein Aggregation and Promoting Disaggregation or Degradation 48 2.4.1 The Small Heat Shock Protein Family (sHsp) 48 2.4.2 The Hsp100/Clp Family of Molecular Chaperones 51 2.5 Heat Shock Proteins are Essential for the Survival of Plasmodium falciparum 53 References 55 Chapter 3: The Role of Hsp70s in the Development and Pathogenicity of Plasmodium falciparum 85 3.1 Introduction 85 3.2 The Role of Plasmodial Heat Shock Proteins at the Host-Parasite Interface 86 3.3 The Structural and Functional Features of Hsp70 87 3.4 Hsp70s from P. falciparum 89 3.5 Cytosol Localised Hsp70s 89 3.5.1 PfHsp70-1 89 3.5.2 PfHsp70-z 92 3.6 Endoplasmic Reticulum Hsp70s 93 3.6.1 PfHsp70-2 93 3.6.2 PfHsp70-y 94 3.6.3 Mitochondrial Hsp70 95 3.7 Exported Hsp70 96 3.7.1 The Role of Parasite Heat Shock Proteins in Host Cell Remodelling 96 3.7.2 PfHsp70-x 96 3.8 Conclusion 98 References 99 Chapter 4: Role of the J Domain Protein Family in the Survival and Pathogenesis of Plasmodium falciparum 106 4.1 Introduction 107 4.1.1 Structural and Functional Features of PfJDPs 107 4.1.2 Implications of the Expanded PfJDP Arsenal 110 4.1.3 Localisation and Expression of PfJDPs in the Malaria Parasite 111 4.2 Parasite-Resident PfJDPs 112 4.2.1 PF14_0359 112 4.2.2 Pfj1 113 4.2.3 Pfj2 117 4.2.4 Pfj4 118 4.2.5 PFB0595w 119 4.3 Exported PfJDPs 119 4.3.1 Protein Export 119 4.3.2 Exported Type II PfJDPs and J-Dots 121 4.3.3 Exported Type III PfJDPs 123 4.3.4 Exported Type IV PfJDPs 124 4.4 PfJDPs as Potential Drug Targets 125 4.5 Conclusion 126 References 127 Chapter 5: Role of Hsp90 in Plasmodium falciparum Malaria 133 5.1 Heat Shock Protein 90: A Potentiator for Pathogen Acclimatization 133 5.2 PfHsp90: Biochemical Characterization 135 5.3 The Role of PfHsp90 in the Cell: Heat Shock and Stage Transition 141 5.4 The Role of Host Hsp90 in P. falciparum Infection 142 5.5 Conclusion 143 References 143 Chapter 6: The Role of Malaria Parasite Heat Shock Proteins in Protein Trafficking and Remodelling of Red Blood Cells 148 6.1 Introduction 149 6.2 The Role of Heat Shock Proteins in the Protein Export Pathway 151 6.2.1 Endoplasmic Reticulum: A Sorting Nexus for Many Destinations 151 6.2.1.1 Import of Proteins into the ER 152 6.2.1.2 Protein Quality Control 156 6.2.1.3 Delivery of Proteins to the Parasitophorous Vacuole That Are Destined for Export 156 6.2.2 Protein Translocation Across the Parasitophorous Vacuole Membrane 156 6.2.2.1 Molecular Mechanism of HSP101 Function 157 6.2.2.2 HSP101 Co-chaperones 157 6.3 The Role of Heat Shock Proteins in Orchestrating Host Cell Renovation 159 6.3.1 Exported JDPs/HSP70-x 160 6.3.2 Host Cell Modifications by Heat Shock Proteins 161 6.3.2.1 Membranous Network and Trafficking Highways Within the Host Cell 161 6.3.2.2 Erythrocyte Deformability 162 6.3.2.3 Recruitment of Host Chaperones 163 6.4 The Role of Heat Shock Chaperones in the Import of Proteins into Organelles of Endosymbiotic Origin 164 6.4.1 The Contribution of Heat Shock Proteins in Protein Trafficking into the Apicoplast 164 6.4.2 Import of Mitochondrial Proteins 166 6.4.2.1 Insertion of Carrier Proteins into the Inner Membrane of Mitochondria 166 6.4.2.2 Import of Proteins into the Matrix of Mitochondria 166 6.5 Conclusions 167 References 168 Chapter 7: Role of Heat Shock Proteins in Immune Modulation in Malaria 175 7.1 Introduction 175 7.2 Parasite Heat Shock Proteins 178 7.3 Host Heat Shock Proteins 181 7.4 Future Perspectives with Respect to New Treatment Strategies for Malaria 184 References 186 Chapter 8: Bioprospecting for Novel Heat Shock Protein Modulators: The New Frontier for Antimalarial Drug Discovery? 193 8.1 Antimalarial Drug Resistance 194 8.2 Heat Shock Proteins as Potential Antimalarial Drug Targets 194 8.3 Structure-Function Features of Hsps That Make Them Amenable to Inhibitor Screening 196 8.4 Plants as Sources of Antimalarial Chemotherapeutic Agents 198 8.5 Natural Compounds Targeting Hsps and Their Prospects as Antimalarials 198 8.5.1 Phenolics 198 8.5.1.1 Chalcones 198 8.5.2 Polyphenols 199 8.5.3 Terpenoids 199 8.5.4 Alkaloids 201 8.5.5 Cyclic Peptides 201 8.5.6 Other Compounds 202 8.6 Various Plant Derived Polyphenols Show Common Inhibitory Mechanisms 202 8.7 Challenges and Opportunities of Identifying and Designing Antimalarial Compounds from Natural Sources 204 References 205 Chapter 9: Heat Shock Proteins as Targets for Novel Antimalarial Drug Discovery 210 9.1 Introduction 211 9.1.1 The Burden of Malaria and Global Efforts in Its Eradication 211 9.1.2 Challenges Posed by the Parasite 213 9.1.3 Targeting HSPs as a Potential Solution 214 9.2 Features of HSPs That Can Be Exploited in Antimalarial Drug Discovery 214 9.2.1 Features of Plasmodial Hsp90 214 9.2.2 Features of Plasmodial Hsp70 215 9.2.3 Features in Plasmodial Hsp40s 217 9.2.4 Features of Plasmodial Hsp60 and Small HSP (sHSP) 217 9.2.5 Functional Interactions as Features for Drug Targeting 218 9.3 Screening Strategies for the Discovery of Small Molecule Inhibitors of Chaperones 224 9.3.1 Introduction 224 9.3.2 Targeting Plasmodial Hsp90 Functional Activities 225 9.3.3 Targeting Hsp70 Functional Activities 226 9.3.4 Targeting Hsp40 Functional Activities 227 9.3.5 Targeting HSPs Functional Interactions 228 9.4 Application of HSPs in High Throughput Antimalarial Drug Screening 229 9.5 Application of HSPs in Computer-Aided Drug Design (CAAD) and Screening 230 9.6 Conclusion 230 References 231 Chapter 10: Heat Shock Proteins of Malaria: Highlights and Future Prospects 242 References 247 Index 252