Molecular and Cellular Aspects of the Serpinopathies and Disorders in Serpin Activity

The following sections are included:

• Contents

• Editors

• Contributors

• Serpinopathies Foreword

• Molecular and Cellular Aspects of the Serpinopathies and Disorders in Serpin Activity
  • Preface
  • Acknowledgments
  • References

The following sections are included:

• Introduction

• The Challenges of Serpin Classification

• The Phylogeny of the Serpin Superfamily
  • The nomenclature of the serpin superfamily

• The Structural Phylogeny of the Serpin Domain
  • Sequence plasticity in the reactive center loop

• Concluding Statements: The Prokaryotic Serpins and the Root of the Serpin Superfamily

• References

The following sections are included:

• Introduction

• Flexibility of the Serpin Native State

• Serpin Structures During Proteinase Inhibition

• Serpin Conformations Associated with Misfolding and Disease

• Stabilization of Serpin Structure Through Interaction with other Molecules

• Conclusions

• References

The following sections are included:

• Introduction

• Detailed Mechanism of Inhibition of Serine Proteinases by Serpins
  • Step 1. recognition of the RCL
  • Step 2. proteolysis of the scissile bond
  • Step 3. Rapid loop insertion and proteinase translocation
  • Step 4. Proteinase crushing/distortion
  • Need for energetic coupling
  • Complex dissociation and stability

• Inhibition of Cysteine Proteinases

• Reversible Inhibition
  • Reversible inhibition by otherwise irreversible serpin inhibitors
  • Reversible inhibition by "non-inhibitory" serpins

• References

The following sections are included:

• Introduction

• The Mouse Serpins and Transgenic Studies
  • Comparison of serpin gene content between mouse and humans
  • Hemostasis and thrombosis systems in mice
  • Regulation of blood pressure and vascular permeability
  • SERPINF1 (PEDF) is a promising therapeutic agent for retinal diseases
  • Identification of intracellular Clade B serpin function in mice
  • Dissection of Serpini1, Serpine2, and Serpine1 activities in the brain
  • Modeling conformational diseases in the mouse

• Conclusions

• References

The following sections are included:

• Introduction

• Distribution of Prokaryotic Serpins

• Evolutionary Relationships

• Structural Features of Prokaryote Serpins

• Serpins in Thermophilic Organisms

• Specificity of Prokaryotic Serpins and Possible Protease Targets

• Conclusions

• Acknowledgments

• References

The following sections are included:

• Introduction

• Selection of Animal Models

• The Properties of Individual Poxvirus Serpins
  • SPI-1 with P1 = Phe
  • The role of P1=Phe serpins in infected animal models
  • SPI-2/crmA and SERP2 with P1 = Asp
  • The role of P1 = Asp serpins in the chicken chorioallantoic membrane
  • The role of P1 = Asp serpins in infected mice
  • The role of P1 = Asp serpins in infected rabbits
  • SPI-3 and SERP1 with P1 = Arg
  • The role of P1-Arg serpins in animal models

• The Use of Virus Serpins as Therapeutic Agents to Control Human Disease

• Clinical Evaluation of SERP1 Administered Locally

• Clinical Evaluation of SERP1 Administered Systemically

• Cellular and Vascular Changes Following SERP1 Treatment

• The use of Gene Therapy to Provide Sustained Delivery of SERP1

• Immune Response to SERP1

• Effect on Thrombotic/Thrombolytic Systems Following Administration of Serp1

• Conclusions

• References

The following sections are included:

• Introduction

• Serpins in C. elegans

• Evolution of C. elegans Serpins

• C. elegans Serpin Gene Structure

• The Biochemistry of SRP-2

• The Biology of SRP-2

• Conclusion

• References

The following sections are included:

• Introduction

• Physiological Functions of Drosophila Serpins
  • Serpins and the innate immune response
  • The Spn42D gene cluster
  • The role of the serpin core and alternatively spliced serpin transcripts
  • Non-inhibitory serpins: Spn28Db, Spn31A, Spn43Ab, Spn43Ad, Spn47C, Spn53F, Spn75F, Spn76A, Spn77Bb, Spn77Bc, Spn85F, and Spn100A

• Structure and Function of the Nec serpin, Spn43Ac
  • In silico prediction of the putative target protease of Nec

• Drosophila Melanogaster as a Model of Human Serpinopathies
  • Homologous mutations in human serpins and Necrotic

• Conclusions

• References

The following sections are included:

• Introduction

• Manduca Serpin-1: 12 Serpins from 1 Gene

• Manduca Serpins 2–7

• Physiological Functions of Manduca Serpins

• Conclusion

• Acknowledgment

• References

The following sections are included:

• Introduction

• MENT Expression and Accumulation in Heterochromatin of Chicken Blood Cells

• MENT cDNA Sequence, Gene, and Chromosomal Location

• MENT Primary Structure and its Relation to Other Proteins

• 3D Structural Modeling of MENT Protein

• Cathepsin L Inhibition

• Chromatin Condensation by MENT

• Mechanism of Chromatin Condensation by MENT: Separate Roles of the M-loop and the RCL Domains
  • The M-loop mediates cooperative DNA binding and nucleosome array folding
  • The RCL domain and linker histone promote self-association of nucleosome arrays in vitro
  • Chromatin-dependent MENT oligomerization requires RCL

• Regulation of MENT Localization and Action Inside the Nuclei
  • Histone modifications
  • Cathepsin L

• References

The following sections are included:

• Introduction

• Uterine Serpin Genes

• Physicochemical Properties

• Tissue Source and Patterns of Secretion During Pregnancy

• Hormonal Regulation of Uterine Serpin Secretion

• Proteinase Inhibitory Activity and Protein Conformation

• Lymphocyte Inhibitory Activity

• Inhibition of Proliferation of Other Cells

• Mechanism of Action of OvUS to Block Cell Proliferation

• Other Activities of Uterine Serpins

• Conclusions

• Acknowledgements

• References

The following sections are included:

• Introduction

• The Beer Connection: A Brief History of Plant Serpin Research

• Serpin Genes in Plant Genomes: Chlamydomonas, Arabidopsis, and Rice

• The QQ Serpins: Glutamine-rich Reactive Centers of Cereal Grain Serpins

• The LR Serpins: A Reactive Center Conserved in Plants

• Vascular Serpins: The Phloem Conduit of Higher Plants

• Target Proteinases: Endogenous or Exogenous?

• Functional Hypothesis 1: Defense Against Pest and Disease Organisms

• Functional Hypothesis 2: Endogenous Proteinase Regulation

• Conclusions

• Note

• References

The following sections are included:

• Introduction to Programmed Cell Death and Apoptosis

• The Caspase Family

• Serpins as Caspase Inhibitors

• Serpins as Cell Death Regulators

• Regulation of Extrinsic Apoptosis Pathway

• Regulation of Intrinsic Apoptosis Pathway

• Lysosomal Death Pathway

• SERPINB5 is a Pro-apoptotic Serpin

• Intracellular Serpins Protect Immune Cells from their Own Cytotoxic Proteases

• Cytotoxic Lymphocytes and Natural Killer Cells

• Granulocytes and Mast Cells

• Conclusions

• References

The following sections are included:

• Introduction

• Structure and Biological Activities of Maspin
  • Biological activities of maspin: Location and function
  • Functional domains of maspin: The reactive site loop
  • Is maspin a protease inhibitor?
  • Mapping functional domains/residues of maspin

• Role of Maspin in Tumor Progression and Angiogenesis
  • Role of maspin in breast cancer progression
  • Role of maspin in angiogenesis

• Clinical Relevance of Maspin in Human Breast and Pancreatic Cancer Specimens

• Other Serpins in Malignancy

• Conclusions

• References

The following sections are included:

• Introduction

• Serpins and Malignant Behavior

• Prognostic Value of Serpins
  • SERPINB2 (PAI-2)
  • SERPINB3 and SERPINB4 (SCCA1 and SCCA2)
  • SERPINB5 (Maspin)
  • SERPINB9 (PI-9)
  • SERPINE1 (PAI-1)
  • SERPINF1 (PEDF)
  • Other SERPINS with prognostic potential

• Conclusions

• Acknowledgment

• References

The following sections are included:

• Introduction

• Mouse Models of Megsin Nephropathy

• Differential Pathology in Megsin Transgenic Rats

• Does Megsin Overexpression Lead to a Serpinopathy?

• Megsin Overexpression and Endoplasmic Reticulum Stress

• Entoplasmic Reticulum Stress and Pancreatic Disease

• ER Stress and Pancreatic Disease

• Conclusions

• References

The following sections are included:

• Introduction

• The LDL Receptor Family

• Serpin-Receptor Interactions

• Serpin Structure Recognized by Signaling Receptors

• Functional Consequences of Receptor Binding

• Binding Interactions of Uncomplexed Serpins

• Non-protease Ligand Binding Domains

• Conclusions

• References

The following sections are included:

• Introduction

• Plasminogen Activator Inhibitor-1 and the Metabolic Syndrome

• α1-Antitrypsin and the Metabolic Syndrome

• Gene Expression of Serpins in Visceral Adipose Tissues of Otsuka Long–Evans Tokushima Fatty Rats

• Production of Recombinant Human Vaspin and its Activity

• Regulation of Vaspin Expression in OLETF Rats

• Vaspin Sensitizes Insulin Action in High Fat High Sucrose Chow-induced Obese ICR Mice

• Vaspin is a New Therapeutic Target of the Metabolic Syndrome

• Acknowledgments

• References

The following sections are included:

• Introduction

• Serpins as a Target for Proteolytic Inactivation through Cleavage of Peptide Bond within the Reactive Site Loop

• Pathological Consequences of Serpin Inactivation by the C10 Family of Pathogen-Derived Proteases

• The Omptins Manipulate the Plasmin/α₂-antiplasmin System

• Exploitation of C1 Inhibitor by StcE, a Metalloprotease Secreted by Escherichia coli O157:H7

• Inhibition of Bacterial Serine Peptidases by Serpins

• Inhibition of Bacterial Cysteine Peptidases by Serpins

• Serpin Direct Functions in the Innate Immunity

• Conclusions

• References

The following sections are included:

• Introduction

• Gain of Function Serpinopathies: α₁-Antitrypsin Deficiency Related Cirrhosis and FENIB
  • PI*Z α₁-antitrypsin deficiency related cirrhosis
  • Familial encephalopathy with neuroserpin inclusion bodies

• Loss of Function Serpinopathies
  • Plasma deficiency of antithrombin, C1 inhibitor, α₁-antichymotrypsin, and heparin co-factor II

• Loss of Function, Gain of Function, and Respiratory Disease
  • Z α₁-antitrypsin deficiency and respiratory disease
  • Extra-pulmonary conditions associated with α₁-antitrypsin deficiency
  • Polymerization of Z α₁-antitrypsin and emphysema

• Conformational Transitions of α₁-Antichymotrypsin and Emphysema

• Treatment of α₁-Antitrypsin Deficiency

• Novel Strategies to Prevent Conformational Transitions and Disease
  • Chemical chaperones to stabilize serpins and block polymerization
  • Filling a surface hydrophobic pocket to block polymerization
  • Peptides with homology to the reactive center loop can compete for binding to β-sheet A and block polymerization

• Acknowledgments

• References

The following sections are included:

• Introduction

• Epidemiology

• Pathogenesis of Liver Injury

• Clinical Characteristics

• Diagnosis

• Treatment

• References

The following sections are included:

• Introduction

• Regulation of Blood Coagulation by Antithrombin, Heparin Cofactor II, Protein C Inhibitor, and Plasminogen Activator Inhibitor-1

• Regulation of the Protein C System by Protein C Inhibitor, Plasminogen Activator Inhibitor-1, and α₁-Antitrypsin

• Regulation of the Fibrinolytic System by Plasminogen Activator Inhibitor-1, α₂-Antiplasmin, Plasminogen Activator Inhibitor-2, and Protein C Inhibitor

• Heparin-binding Serpins: Antithrombin, Heparin Cofactor II, and Protein C Inhibitor
  • Antithrombin properties and function
  • Mechanisms of heparin activation of antithrombin
  • Molecular details of the antithrombin–heparin interaction
  • Reactive center loop structural changes induced by heparin activation
  • Mechanism of transmission of conformational change from the heparin binding site to the RCL
  • Role of the RCL in determining antithrombin specificity for proteases
  • Antiangiogenic activity of conformationally altered forms of antithrombin
  • Heparin cofactor II, properties and function
  • Reactive center loop and acidic domain of heparin cofactor II
  • Glycosaminoglycan-binding site of heparin cofactor II
  • Mechanism of glycosaminoglycan activation of heparin cofactor II
  • Extravascular thrombin regulation by heparin cofactor II
  • Protein C inhibitor, properties and function
  • Glycosaminoglycan-binding site of protein C inhibitor
  • Mechanism of glycosaminoglycan acceleration of protein C inhibitor

• Serpin Knockout and Transgenic Mice
  • Antithrombin
  • Heparin cofactor II
  • Protein C inhibitor

• Acknowledgments

• References

The following sections are included:

• Introduction

• Structure of C1-inhibitor

• Inhibitory Specificity of C1-inhibitor

• Synthesis of C1-inhibitor

• The Biologic Importance of C1-inhibitor

• Hereditary Angioedema

• C1-Inhibitor Deficient Mice

• C1-inhibitor Functions that do not Depend on Protease Inhibition

• The Interaction of C1-Inhibitor with Gram-Negative Endotoxin

• The Effect of C1-inhibitor on Leukocyte Migration

• The Binding of C1 Inhibitor to Extracellular Matrix Components

• C1-inhibitor Mediated Suppression of Alternative Complement Pathway Activation

• Therapeutic Uses of C1-inhibitor

• Conclusions

• References

The following section are included:

• Introduction

• Genetics of Neuroserpin

• Biochemical Properties of Neuroserpin

• Distribution of Neuroserpin in the Central Nervous System
  • Neuroserpin in the developing CNS
  • Neuroserpin in the adult CNS

• Neuroserpin in Normal CNS Function
  • Synaptic plasticity
  • Behavior

• Neuroserpin in CNS Disease
  • Cerebrovascular disease
  • TPA and neuroserpin in cerebral ischemia
  • Neuroprotective role of neuroserpin in cerebral ischemia
  • Effects of neuroserpin on ischemia-induced increases in blood brain barrier permeability
  • Seizures
  • Role of tPA and neuroserpin in seizures
  • Neuroprotective effect of neuroserpin on seizures-induced cell death

• Familial Encephalopathy with Neuroserpin Inclusion Bodies (FENIB)
  • Neuropathology
  • Genetics and pathophysiology of FENIB
  • Clinical manifestations

• Conclusions

• References

The following sections are included:

• Introduction

• Brain Distribution and Forms of ACT

• Effects of ACT on Aβ Fibrillization

• Transgenic Models for the in vivo Role of α₁-Antichymotrypsin in Alzheimer's Disease

• Alzheimer's Disease and the Genetics of ACT

• ACT as a Diagnostic Marker for Alzheimer's Disease

• Serpins and Proteolytic Degradation of Aβ

• Activity Gain and Loss from the ACT – Aβ Interaction

• Conclusion

• References

The following sections are included:

• Index