Macromolecular Protein Complexes II: Structure and Function (Subcellular Biochemistry, 93) 9783030281502, 9783030281519, 3030281507

Table of contents :
Preface
Contents
1 Introduction: Protein Oligomerization and the Formation of Macromolecular Assemblies
Abstract
Fundamentals
The Structural Techniques
Some Oligomeric Proteins and Complexes
Hemoglobin
The Haemocyanins
The Peroxiredoxins
Collagen Assemblies
Collagen Fibrils and SLS Crystallites
High-Resolution Studies of Model Proteins
Encapsulins
References
2 Antibody Complexes
Abstract
Introduction
Structure of Antibodies
IgM
IgA
IgE
IgD
IgG
Diversity and Flexibility in Antibodies
3D Structure of IgG Antibodies and Its Conformational Diversity
3D Structure of IgM
Ebola Virus
Human Immunmodefficiency Virus: HIV
Hepatitis C Virus: HCV
Malaria
Conclusion and Perspective
References
3 Unravelling Ribosome Function Through Structural Studies
Abstract
Why We Need to Study Ribosomes
Methods Used in Studies of Ribosome Structure/Function Relationship
General Organisation of Ribosomes in Prokaryotes
Structural Basis of Protein Synthesis by the Ribosome
Initiation
Elongation
Termination
Recycling
Regulatory Co-translational Events at the Ribosome Exit Tunnel
Future Prospects
Acknowledgements
References
4 Functions and Mechanisms of the Human Ribosome-Translocon Complex
Abstract
Introduction: Structure, Function, Dynamics and Connectivity of the Mammalian Endoplasmic Reticulum (ER)
Structures and Functions of Isolated and Native Sec61 Complexes
Structural Esthetics of the Sec61 Complex
Structural Dynamics of the Sec61 Complex
Functions of the Mammalian Sec61 Complex
Architecture of the Native Sec61 Complex, the Translocon
The Role of Allosteric Effectors of the Eukaryotic Sec61 Complex Previously Visualized by Structural Biology
The Ribosome
The TRAP Complex
The OST Complex
The Sec62/63 Complex
Additional Transport Components and Allosteric Effectors of the Sec61 Channel
BiP, an Additional Allosteric Sec61 Channel Effector
Auxiliary Transport Components of the ER Membrane
Additional Allosteric Effectors in the Cytosol Interacting with the Sec61 Complex
Small Molecules Directly Interfering with the Sec61 Complex
Modalities of Precursor Targeting Factors Delivering Substrates to the Translocon
Targeting of Precursor Polypeptides to the Sec61 Complex in the ER Membrane
Targeting of mRNAs to the ER Membrane
Additional Putative Functions of the Human Sec61 Channel
Open Question
Systematic Knock Down of ER-Protein Translocation Machinery Components in Human Cells Combined with Characterization of Substrate Precursor Proteins and Compensatory Mechanisms by Quantitative Proteomic Analysis
Integrative Determination of the Molecular Architecture of the Native ER Translocon Core Complexes
References
5 The Structures of Eukaryotic Transcription Pre-initiation Complexes and Their Functional Implications
Abstract
Introduction to Transcription in Eukaryotes
The Pol II Pre-initiation Complex
Pol II and the General Transcription Factors
TFIID
Function of TFIID
Conformational Complexity of TFIID
The Structure of TFIID
Mechanism of TBP Loading onto the Promoter
TFIIH
Functional Roles of TFIIH in Transcription
TFIIH as a DNA Repair Complex
The Structure of TFIIH
TFIIH in Health and Disease
Structural Insight into the Pol II-PIC
Visualization of the Step-Wise Assembly of the Human Pol II-PIC
High-Resolution Analysis of the Pol II Core-PIC and Mechanism of Open Complex Formation
The Mediator-Bound Pol II PIC
Possible Organization of a Complete Pol II-PIC Containing TFIID and Mediator
The Pol I and Pol III Pre-initiation Complexes
Structure of the Pol I-PIC and Mechanism of Initiation of rRNA Transcription
Pol I and Its General Transcription Factors
Structural Insight into RNA Polymerase I Pre-initiation Complexes
Model for Initiation by RNA Polymerase I
Structure of the Pol III-PIC and Similarities to the Pol II System
Pol III and Its Redox-Sensing General Transcription Factor TFIIIB
The Structure of the RNA Polymerase III Pre-initiation Complex
Model for Transcription Initiation by RNA Polymerase III and Transition to Elongation
Comparison of PIC Architectures
Conserved and Divergent Features of Eukaryotic Pre-initiation Complex Architectures
Universality of TFIIB-like Factors and Positioning of the Promoter DNA in the PIC
Built-in General Transcription Factor-like Subunits in Pol I and Pol III
Opening of the Transcription Bubble
Open Complex Formation in Yeast
The Mammalian RNA Polymerase System
Conclusion
Acknowledgements
References
6 Regulation of Antiviral Innate Immunity Through APOBEC Ribonucleoprotein Complexes
Abstract
The APOBEC3 Proteins in Innate Antiviral Immunity
APOBEC3 Antiviral Mechanism
HIV Vif-Dependent Proteosomal Degradation of A3 Reduces Innate Antiviral Immunity
RNA Binding to A3G Can Inhibit Deaminase Activity
Biochemical Analysis of A3 Interactions with Nucleic Acids
Emergence of the Dual RNA-Binding Domain Hypothesis
The Functional Significance of the RNA Binding Partner for A3G
The RNA Binding Preference of A3G Changes Following HIV Infection
RNA Binding of A3G Paradoxically May Both Inhibit and Promote Antiviral Deaminase Activity
Structural Models of APOBECs Suggest Mechanisms for Nucleic Acid Binding
Nearest Neighbor Base Sequence Determines APOBEC Target Specificity
AID Selects Structured DNA Substrates
DNA Binding Sites Distal to the APOBEC Active Site May Assist Substrate Selection
RNP Formation with APOBECs Regulate Enzymatic Activity
Concluding Remarks
References
7 Structure and Function of the AAA+ ATPase p97, a Key Player in Protein Homeostasis
Abstract
Introduction
Structure and Conformational Changes of p97
Macromolecular p97–Cofactor Complexes
p97 Cofactor Interaction Modes
Regulation of p97 Cofactor Assembly
p97–Cofactor Complexes Involved in Diverse Cellular Functions
Mechanistic Insights into p97 Function
p97 as a Potential Drug Target in Cancer Therapy
Targeting PQC Pathways in Cancer Therapy
p97 Inhibitors
p97 Cofactors as Potential Drug Targets
Proteomic Approaches to Analyze the p97 Interactome
Conclusions and Future Perspectives
Acknowledgements
References
8 Penicillin-Binding Proteins (PBPs) and Bacterial Cell Wall Elongation Complexes
Abstract
Introduction
Fold and Functions of Penicillin-Binding Proteins (PBPs)
PBP Interactions Within the Elongasome/Rod Complex
Regulation of Cell Wall Elongation
Partnerships with Other Inner Membrane Proteins
Interactions with the Outer Membrane
Concluding Remarks
Acknowledgements
References
9 Structure and Function of Roundabout Receptors
Abstract
Introduction
The Robo Receptor Family
Slit Proteins Are Robo1/Robo2 Receptor Ligands
Heparan Binding
Robo3
Robo4
Robo Co-receptors
Robo Signalling Mechanism
Concluding Remarks
References
10 Structure and Function of Molecular Chaperones that Govern Immune Peptide Loading
Abstract
Introduction
MHC Molecules, Peptide Binding Ligands for TCR
Peptide Loading in the MHC-I Pathway
Structure of Tapasin/ERp57
Low Resolution Structures of Tapasin and TAPBPR
X-Ray Structures of TAPBPR
Functional and Structural Examination of the 22 to 35 Loop Region of TAPBPR and Tapasin
Cryo-EM Structure of the PLC
Assessing the Dynamics of MHC/TAPBPR Interaction with NMR
Conclusions
Acknowledgements
References
11 Biology and Biochemistry of Bacterial Proteasomes
Abstract
Introduction
20S Proteasome Core Particles
ATP-Dependent Proteasome Activation
Pup: A Degradation Signal, and More
Pupylation
Delivery of Pupylated Proteins to the Proteasome
Fate of Pup: Depupylation and Transpupylation
Degradation-Independent Functions of Pupylation
ATP-Independent Proteasome Activation
Roles of the Proteasome in Bacterial Physiology
Nitric Oxide Resistance
Copper Homeostasis
Protein Quality Control
Nitrogen Metabolism
Remaining Questions
Acknowledgements
References
12 The Kai-Protein Clock—Keeping Track of Cyanobacteria’s Daily Life
Abstract
Circadian Clocks
The Kai-Protein System of Synechococcus Elongatus
Structures of the Kai Proteins
KaiC
KaiB
KaiA
Input and Output Protein Factors
Feedback Mechanisms and Entrainment
Diversity and Evolution of Kai-Protein System
Outlook
References
13 Frataxin Structure and Function
Abstract
Friedreich’s Ataxia and the History of Frataxin: Why This Chapter is Focused on Frataxin
The Long Path from Structure to Function: FXN Is Involved in Iron–Sulfur Cluster Assembly
Conformational Stability, Internal Motions and Folding Dynamics
Understanding the Effect of Mutations on Structural Dynamics
Mutation G130V
G137V Mutation
L198R Mutation
W155R Mutation
N146K Mutation
D122Y Mutation
FXN Degradation Inside the Cell
Iron Binding and Function
A Macromolecular Context for FXN in Iron–Sulfur Cluster Biosynthesis
Activator in Eukaryotes, Inhibitor in Prokaryotes: Differences in the Role of FXN in the Fe-S Clusters Biosynthesis
FXN as a Scaffold to Form Oligomers and Nanoparticles
Conclusions
Acknowledgements
References
14 Crystallins and Their Complexes
Abstract
Crystallin Proteins of Eye Lens
βγ-Crystallins
β-Crystallins
γ-Crystallins
γC-Crystallin
γD-Crystallin
γS-Crystallin
α-Crystallin
Structure of α-Crystallins
Domain Organization
α-Crystallin Domain (ACD)
N-Terminal Region (NTR)
C-Terminal Region (CTR)
Crystallin Complexes
References
15 Structure and Function of the TREX-2 Complex
Abstract
Biological Function of the TREX-2 Complex
Composition and Structure of the TREX-2 Complex
Structure of the TREX-2 C-Terminal CID Domain
The TREX-2 Central M-Region
The TREX-2 N-Terminal Region
Summary and Questions Outstanding
Acknowledgements
References
16 Amyloid Oligomers, Protofibrils and Fibrils
Abstract
Introduction
Protein Folding and Aggregation Are Competing Processes
General Structural Features of Amyloid Oligomers, Protofibrils and Fibrils
Characterization of Amyloid Oligomers, Protofibrils and Fibrils
Electrophoresis
Analytical Ultracentrifugation
Size Exclusion Chromatography
Mass Spectrometry and Ion Mobility Mass Spectrometry
Turbidity and Light Scattering Analysis
Dyes and Extrinsic Fluorescent Probes
Imaging Method
Circular Dichroism Measurements
Nuclear Magnetic Resonance Spectroscopy
Immunochemical Methods
Toxicity of Oligomer, Protofibrils and Mature Fibrils
Cellular Mechanism of Toxicity
Membrane Interaction
Perturbation of Calcium Homeostasis
Intermediary Oligomers as Potential Biomarkers
Amyloid Inhibition Strategies
Inhibition of the Accumulation of Peptide/Protein Monomers
Targeting Protein Misfolding
Stabilization of Native Conformation (Induction of Physiological Chaperones)
Interference with the Transition Process (Peptide Based Inhibitors and Small Synthetic Compounds)
Inhibition of Pathological Chaperones
Reduction of Soluble Oligomers
Inhibition of Oligomerisation Pathway
Over-Acceleration of Oligomer Aggregation
Promotion of Fibril Clearance
Regulation of Ubiquitin Proteasome System and Autophagy
Activation of Specific Proteases or Clearing Enzymes
Therapeutics Under Clinical Trials
Conclusion
Acknowledgements
References
17 CAD, A Multienzymatic Protein at the Head of de Novo Pyrimidine Biosynthesis
Abstract
The de Novo Biosynthetic Pathway for Pyrimidines
Starting from the Beginning: The GLN and SYN Domains
GLN Domain
SYN Domain
Allosteric Regulation
A Reaction Tunnel
A Cooperative ATC Domain
A DHO Domain in the Midst of CAD
Putting the Pieces Together for the Pyrimidine Factory
CAD in Human Diseases
References
18 The Anaphase Promoting Complex/Cyclosome (APC/C): A Versatile E3 Ubiquitin Ligase
Abstract
Introduction
Structural Architecture
APC/C Regulation Is Intricate
Cell-Cycle-Independent Functions of APC/C E3 Ligase
An Incipient Role of the APC/C in Alzheimer’s Disease?
APC/C Association with the Ectopic Cycle in AD
APC/C Involvement in Oxidative Stress in AD
APC/C Connection with Excitotoxicity in AD
APC/C Contribution to Long-Term Potentiation Impairment in AD
APC/C Implications in Neurogenesis Impairment in AD
Manipulation of the APC/C by Viruses
Human T-Cell Lymphotropic Virus Type 1 Tax
Hepatitis B Virus X
Orf Virus PACR
Human Papillomavirus E2
Chicken Anemia Virus Apoptin
Adenovirus E1A
Adenovirus E4orf4
Human Cytomegalovirus PUL97
Human Cytomegalovirus Virus PUL21a
Other Demonstrations of Viruses Manipulating the APC/C
APC/C Deregulation Drives Carcinogenesis
APC/C Coactivators Association with Tumorigenesis
APC/C Inhibitors Contribution to Oncogenic Transformation
APC/C as an Attractive Therapeutic Target
Concluding Remarks and Perspective Analysis
References
19 TRiC/CCT Chaperonin: Structure and Function
Abstract
Introduction
TRiC Molecular Structure
Structural Studies of TRiC and Its ATP-Driven Conformational Cycle
TRiC Subunit Arrangement
Structural Study on TRiC with Substrate
Key Structural Elements of Group II Chaperonin
Structure of TRiC with Co-chaperone
Cryo-ET of TRiC with Substrate
Structure of Mutated TRiC and Homo-Oligomer of TRiC Single Subunit
Functions of TRiC
Substrate Folding Assisted by TRiC
TRiC and Diseases
TRiC and Neurodegenerative Diseases
TRiC and Eye Related Diseases
TRiC and Cancer
Potential Therapeutic Applications of TRiC
TRiC Subunit Can Serve as a Biomarker for Related Disease
Potential Application of TRiC in Preventing MHtt (Mutant Huntingtin) Aggregation
TRiC Is a Potential Target for Therapeutic Intervention
Perspective
Author Declaration
References
Index