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

Preface\nContents\n1 Introduction: Protein Oligomerization and the Formation of Macromolecular Assemblies\n	Abstract\n	Fundamentals\n	The Structural Techniques\n	Some Oligomeric Proteins and Complexes\n		Hemoglobin\n		The Haemocyanins\n		The Peroxiredoxins\n		Collagen Assemblies\n			Collagen Fibrils and SLS Crystallites\n	High-Resolution Studies of Model Proteins\n		Encapsulins\n	References\n2 Antibody Complexes\n	Abstract\n	Introduction\n	Structure of Antibodies\n		IgM\n		IgA\n		IgE\n		IgD\n		IgG\n	Diversity and Flexibility in Antibodies\n	3D Structure of IgG Antibodies and Its Conformational Diversity\n	3D Structure of IgM\n	Ebola Virus\n	Human Immunmodefficiency Virus: HIV\n	Hepatitis C Virus: HCV\n	Malaria\n	Conclusion and Perspective\n	References\n3 Unravelling Ribosome Function Through Structural Studies\n	Abstract\n	Why We Need to Study Ribosomes\n	Methods Used in Studies of Ribosome Structure/Function Relationship\n	General Organisation of Ribosomes in Prokaryotes\n	Structural Basis of Protein Synthesis by the Ribosome\n		Initiation\n		Elongation\n		Termination\n		Recycling\n	Regulatory Co-translational Events at the Ribosome Exit Tunnel\n	Future Prospects\n	Acknowledgements\n	References\n4 Functions and Mechanisms of the Human Ribosome-Translocon Complex\n	Abstract\n	Introduction: Structure, Function, Dynamics and Connectivity of the Mammalian Endoplasmic Reticulum (ER)\n	Structures and Functions of Isolated and Native Sec61 Complexes\n		Structural Esthetics of the Sec61 Complex\n		Structural Dynamics of the Sec61 Complex\n		Functions of the Mammalian Sec61 Complex\n		Architecture of the Native Sec61 Complex, the Translocon\n	The Role of Allosteric Effectors of the Eukaryotic Sec61 Complex Previously Visualized by Structural Biology\n		The Ribosome\n		The TRAP Complex\n		The OST Complex\n		The Sec62/63 Complex\n	Additional Transport Components and Allosteric Effectors of the Sec61 Channel\n		BiP, an Additional Allosteric Sec61 Channel Effector\n		Auxiliary Transport Components of the ER Membrane\n		Additional Allosteric Effectors in the Cytosol Interacting with the Sec61 Complex\n	Small Molecules Directly Interfering with the Sec61 Complex\n	Modalities of Precursor Targeting Factors Delivering Substrates to the Translocon\n		Targeting of Precursor Polypeptides to the Sec61 Complex in the ER Membrane\n		Targeting of mRNAs to the ER Membrane\n	Additional Putative Functions of the Human Sec61 Channel\n	Open Question\n		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\n		Integrative Determination of the Molecular Architecture of the Native ER Translocon Core Complexes\n	References\n5 The Structures of Eukaryotic Transcription Pre-initiation Complexes and Their Functional Implications\n	Abstract\n	Introduction to Transcription in Eukaryotes\n	The Pol II Pre-initiation Complex\n		Pol II and the General Transcription Factors\n		TFIID\n			Function of TFIID\n			Conformational Complexity of TFIID\n			The Structure of TFIID\n			Mechanism of TBP Loading onto the Promoter\n		TFIIH\n			Functional Roles of TFIIH in Transcription\n			TFIIH as a DNA Repair Complex\n			The Structure of TFIIH\n			TFIIH in Health and Disease\n		Structural Insight into the Pol II-PIC\n			Visualization of the Step-Wise Assembly of the Human Pol II-PIC\n			High-Resolution Analysis of the Pol II Core-PIC and Mechanism of Open Complex Formation\n			The Mediator-Bound Pol II PIC\n			Possible Organization of a Complete Pol II-PIC Containing TFIID and Mediator\n	The Pol I and Pol III Pre-initiation Complexes\n		Structure of the Pol I-PIC and Mechanism of Initiation of rRNA Transcription\n			Pol I and Its General Transcription Factors\n			Structural Insight into RNA Polymerase I Pre-initiation Complexes\n			Model for Initiation by RNA Polymerase I\n		Structure of the Pol III-PIC and Similarities to the Pol II System\n			Pol III and Its Redox-Sensing General Transcription Factor TFIIIB\n			The Structure of the RNA Polymerase III Pre-initiation Complex\n			Model for Transcription Initiation by RNA Polymerase III and Transition to Elongation\n	Comparison of PIC Architectures\n		Conserved and Divergent Features of Eukaryotic Pre-initiation Complex Architectures\n			Universality of TFIIB-like Factors and Positioning of the Promoter DNA in the PIC\n			Built-in General Transcription Factor-like Subunits in Pol I and Pol III\n		Opening of the Transcription Bubble\n			Open Complex Formation in Yeast\n			The Mammalian RNA Polymerase System\n	Conclusion\n	Acknowledgements\n	References\n6 Regulation of Antiviral Innate Immunity Through APOBEC Ribonucleoprotein Complexes\n	Abstract\n	The APOBEC3 Proteins in Innate Antiviral Immunity\n		APOBEC3 Antiviral Mechanism\n		HIV Vif-Dependent Proteosomal Degradation of A3 Reduces Innate Antiviral Immunity\n		RNA Binding to A3G Can Inhibit Deaminase Activity\n	Biochemical Analysis of A3 Interactions with Nucleic Acids\n		Emergence of the Dual RNA-Binding Domain Hypothesis\n		The Functional Significance of the RNA Binding Partner for A3G\n		The RNA Binding Preference of A3G Changes Following HIV Infection\n	RNA Binding of A3G Paradoxically May Both Inhibit and Promote Antiviral Deaminase Activity\n	Structural Models of APOBECs Suggest Mechanisms for Nucleic Acid Binding\n		Nearest Neighbor Base Sequence Determines APOBEC Target Specificity\n		AID Selects Structured DNA Substrates\n		DNA Binding Sites Distal to the APOBEC Active Site May Assist Substrate Selection\n		RNP Formation with APOBECs Regulate Enzymatic Activity\n	Concluding Remarks\n	References\n7 Structure and Function of the AAA+ ATPase p97, a Key Player in Protein Homeostasis\n	Abstract\n	Introduction\n	Structure and Conformational Changes of p97\n	Macromolecular p97–Cofactor Complexes\n		p97 Cofactor Interaction Modes\n		Regulation of p97 Cofactor Assembly\n		p97–Cofactor Complexes Involved in Diverse Cellular Functions\n	Mechanistic Insights into p97 Function\n	p97 as a Potential Drug Target in Cancer Therapy\n		Targeting PQC Pathways in Cancer Therapy\n		p97 Inhibitors\n		p97 Cofactors as Potential Drug Targets\n	Proteomic Approaches to Analyze the p97 Interactome\n	Conclusions and Future Perspectives\n	Acknowledgements\n	References\n8 Penicillin-Binding Proteins (PBPs) and Bacterial Cell Wall Elongation Complexes\n	Abstract\n	Introduction\n	Fold and Functions of Penicillin-Binding Proteins (PBPs)\n	PBP Interactions Within the Elongasome/Rod Complex\n	Regulation of Cell Wall Elongation\n	Partnerships with Other Inner Membrane Proteins\n	Interactions with the Outer Membrane\n	Concluding Remarks\n	Acknowledgements\n	References\n9 Structure and Function of Roundabout Receptors\n	Abstract\n	Introduction\n	The Robo Receptor Family\n	Slit Proteins Are Robo1/Robo2 Receptor Ligands\n	Heparan Binding\n	Robo3\n	Robo4\n	Robo Co-receptors\n	Robo Signalling Mechanism\n	Concluding Remarks\n	References\n10 Structure and Function of Molecular Chaperones that Govern Immune Peptide Loading\n	Abstract\n	Introduction\n	MHC Molecules, Peptide Binding Ligands for TCR\n	Peptide Loading in the MHC-I Pathway\n	Structure of Tapasin/ERp57\n	Low Resolution Structures of Tapasin and TAPBPR\n	X-Ray Structures of TAPBPR\n	Functional and Structural Examination of the 22 to 35 Loop Region of TAPBPR and Tapasin\n	Cryo-EM Structure of the PLC\n	Assessing the Dynamics of MHC/TAPBPR Interaction with NMR\n	Conclusions\n	Acknowledgements\n	References\n11 Biology and Biochemistry of Bacterial Proteasomes\n	Abstract\n	Introduction\n	20S Proteasome Core Particles\n	ATP-Dependent Proteasome Activation\n	Pup: A Degradation Signal, and More\n		Pupylation\n		Delivery of Pupylated Proteins to the Proteasome\n		Fate of Pup: Depupylation and Transpupylation\n		Degradation-Independent Functions of Pupylation\n	ATP-Independent Proteasome Activation\n	Roles of the Proteasome in Bacterial Physiology\n		Nitric Oxide Resistance\n		Copper Homeostasis\n		Protein Quality Control\n		Nitrogen Metabolism\n	Remaining Questions\n	Acknowledgements\n	References\n12 The Kai-Protein Clock—Keeping Track of Cyanobacteria’s Daily Life\n	Abstract\n	Circadian Clocks\n	The Kai-Protein System of Synechococcus Elongatus\n	Structures of the Kai Proteins\n		KaiC\n		KaiB\n		KaiA\n	Input and Output Protein Factors\n	Feedback Mechanisms and Entrainment\n	Diversity and Evolution of Kai-Protein System\n	Outlook\n	References\n13 Frataxin Structure and Function\n	Abstract\n	Friedreich’s Ataxia and the History of Frataxin: Why This Chapter is Focused on Frataxin\n	The Long Path from Structure to Function: FXN Is Involved in Iron–Sulfur Cluster Assembly\n	Conformational Stability, Internal Motions and Folding Dynamics\n		Understanding the Effect of Mutations on Structural Dynamics\n		Mutation G130V\n		G137V Mutation\n		L198R Mutation\n		W155R Mutation\n		N146K Mutation\n		D122Y Mutation\n	FXN Degradation Inside the Cell\n	Iron Binding and Function\n	A Macromolecular Context for FXN in Iron–Sulfur Cluster Biosynthesis\n	Activator in Eukaryotes, Inhibitor in Prokaryotes: Differences in the Role of FXN in the Fe-S Clusters Biosynthesis\n	FXN as a Scaffold to Form Oligomers and Nanoparticles\n	Conclusions\n	Acknowledgements\n	References\n14 Crystallins and Their Complexes\n	Abstract\n	Crystallin Proteins of Eye Lens\n	βγ-Crystallins\n		β-Crystallins\n		γ-Crystallins\n			γC-Crystallin\n			γD-Crystallin\n			γS-Crystallin\n		α-Crystallin\n			Structure of α-Crystallins\n			Domain Organization\n				α-Crystallin Domain (ACD)\n				N-Terminal Region (NTR)\n				C-Terminal Region (CTR)\n	Crystallin Complexes\n	References\n15 Structure and Function of the TREX-2 Complex\n	Abstract\n	Biological Function of the TREX-2 Complex\n	Composition and Structure of the TREX-2 Complex\n		Structure of the TREX-2 C-Terminal CID Domain\n		The TREX-2 Central M-Region\n		The TREX-2 N-Terminal Region\n	Summary and Questions Outstanding\n	Acknowledgements\n	References\n16 Amyloid Oligomers, Protofibrils and Fibrils\n	Abstract\n	Introduction\n	Protein Folding and Aggregation Are Competing Processes\n	General Structural Features of Amyloid Oligomers, Protofibrils and Fibrils\n	Characterization of Amyloid Oligomers, Protofibrils and Fibrils\n		Electrophoresis\n		Analytical Ultracentrifugation\n		Size Exclusion Chromatography\n		Mass Spectrometry and Ion Mobility Mass Spectrometry\n		Turbidity and Light Scattering Analysis\n		Dyes and Extrinsic Fluorescent Probes\n		Imaging Method\n		Circular Dichroism Measurements\n		Nuclear Magnetic Resonance Spectroscopy\n		Immunochemical Methods\n	Toxicity of Oligomer, Protofibrils and Mature Fibrils\n	Cellular Mechanism of Toxicity\n		Membrane Interaction\n		Perturbation of Calcium Homeostasis\n		Intermediary Oligomers as Potential Biomarkers\n	Amyloid Inhibition Strategies\n		Inhibition of the Accumulation of Peptide/Protein Monomers\n		Targeting Protein Misfolding\n			Stabilization of Native Conformation (Induction of Physiological Chaperones)\n			Interference with the Transition Process (Peptide Based Inhibitors and Small Synthetic Compounds)\n			Inhibition of Pathological Chaperones\n		Reduction of Soluble Oligomers\n			Inhibition of Oligomerisation Pathway\n			Over-Acceleration of Oligomer Aggregation\n		Promotion of Fibril Clearance\n			Regulation of Ubiquitin Proteasome System and Autophagy\n			Activation of Specific Proteases or Clearing Enzymes\n	Therapeutics Under Clinical Trials\n	Conclusion\n	Acknowledgements\n	References\n17 CAD, A Multienzymatic Protein at the Head of de Novo Pyrimidine Biosynthesis\n	Abstract\n	The de Novo Biosynthetic Pathway for Pyrimidines\n	Starting from the Beginning: The GLN and SYN Domains\n		GLN Domain\n		SYN Domain\n		Allosteric Regulation\n		A Reaction Tunnel\n	A Cooperative ATC Domain\n	A DHO Domain in the Midst of CAD\n	Putting the Pieces Together for the Pyrimidine Factory\n	CAD in Human Diseases\n	References\n18 The Anaphase Promoting Complex/Cyclosome (APC/C): A Versatile E3 Ubiquitin Ligase\n	Abstract\n	Introduction\n	Structural Architecture\n	APC/C Regulation Is Intricate\n	Cell-Cycle-Independent Functions of APC/C E3 Ligase\n	An Incipient Role of the APC/C in Alzheimer’s Disease?\n		APC/C Association with the Ectopic Cycle in AD\n		APC/C Involvement in Oxidative Stress in AD\n		APC/C Connection with Excitotoxicity in AD\n		APC/C Contribution to Long-Term Potentiation Impairment in AD\n		APC/C Implications in Neurogenesis Impairment in AD\n	Manipulation of the APC/C by Viruses\n		Human T-Cell Lymphotropic Virus Type 1 Tax\n		Hepatitis B Virus X\n		Orf Virus PACR\n		Human Papillomavirus E2\n		Chicken Anemia Virus Apoptin\n		Adenovirus E1A\n		Adenovirus E4orf4\n		Human Cytomegalovirus PUL97\n		Human Cytomegalovirus Virus PUL21a\n		Other Demonstrations of Viruses Manipulating the APC/C\n	APC/C Deregulation Drives Carcinogenesis\n		APC/C Coactivators Association with Tumorigenesis\n		APC/C Inhibitors Contribution to Oncogenic Transformation\n	APC/C as an Attractive Therapeutic Target\n	Concluding Remarks and Perspective Analysis\n	References\n19 TRiC/CCT Chaperonin: Structure and Function\n	Abstract\n	Introduction\n	TRiC Molecular Structure\n		Structural Studies of TRiC and Its ATP-Driven Conformational Cycle\n		TRiC Subunit Arrangement\n		Structural Study on TRiC with Substrate\n		Key Structural Elements of Group II Chaperonin\n		Structure of TRiC with Co-chaperone\n		Cryo-ET of TRiC with Substrate\n		Structure of Mutated TRiC and Homo-Oligomer of TRiC Single Subunit\n	Functions of TRiC\n		Substrate Folding Assisted by TRiC\n		TRiC and Diseases\n			TRiC and Neurodegenerative Diseases\n			TRiC and Eye Related Diseases\n			TRiC and Cancer\n		Potential Therapeutic Applications of TRiC\n			TRiC Subunit Can Serve as a Biomarker for Related Disease\n			Potential Application of TRiC in Preventing MHtt (Mutant Huntingtin) Aggregation\n			TRiC Is a Potential Target for Therapeutic Intervention\n	Perspective\n	Author Declaration\n	References\nIndex