The Networking of Chaperones by Co-Chaperones

Preface
Acknowledgements
Contents
Editors and Contributors
Chapter 1: Nucleotide Exchange Factors for Hsp70 Molecular Chaperones: GrpE, Hsp110/Grp170, HspBP1/Sil1, and BAG Domain Protei...
	Introduction
	Hsp70 Architecture and Functional Cycle
	DnaK, DnaJ, and GrpE: The Eubacterial Hsp70 System
	The Evolution of the Eukaryotic Hsp70 Systems
	Molecular Structure and Function of Eukaryotic NEFs
		Eukaryotic GrpE Homologs
		The Hsp110 Family of Nucleotide Exchange Factors
		Sil1/HspBP1 Homologs
		BAG Domain-Containing NEFs
	ADP Dissociation Inhibitors: Antagonists of Hsp70-NEF Function
	Cellular Functions of NEF Proteins in S. cerevisiae
	Aspects of NEF Function in Mammalian Protein Folding and Quality Control
	Conclusions
	References
Chapter 2: Functions of the Hsp90-Binding FKBP Immunophilins
	Introduction
	Structure/Function Relationships of Steroid Receptor-Associated FKBPs
	Cellular and Physiological Functions of Hsp90-Associated FKBPs
		FKBP52
		FKBP51
		TPR-Domain Immunophilins Regulate the Subcellular Localization of Soluble Proteins
	Xap2
	FKBP36
	FKBP38
	FKBPL
	Plant FKBPs
	Summary
	References
Chapter 3: Hsp70/Hsp90 Organising Protein (Hop): Coordinating Much More than Chaperones
	Assisted Protein Folding by the Hsp70/Hsp90 Chaperone Complex
	Hop (Hsp70-Hsp90 Organising Protein)
	Structure of Hop
	Functions of Hop
		Hop as a Co-chaperone for Hsp70 and Hsp90: A Shift in the Paradigm
		Extracellular Hop Has Cytokine-Like Activity
		Hop in Human Cellular Function and Disease
			Cancer Cell Biology
			Hop as a Therapeutic Target for Cancer
	Developmental and Protein Folding Disorders
	Parasitic Diseases
	Conclusion
	References
Chapter 4: Specification of Hsp70 Function by Hsp40 Co-chaperones
	Introduction
	A. Hsp70 Co-chaperone Activity of Hsp40s
	B. How Does the J-Domain Regulate Client Binding by Hsp70
	C. Do Hsp40s Act as Chaperones?
	C. Determination of Hsp70 Functional Specificity
	D. Hsp40 Quaternary Structure
	E. ER-Transmembrane Hsp40s and Membrane Protein Quality Control
	F. Hsp40s into the Future
	References
Chapter 5: Cdc37 as a Co-chaperone to Hsp90
	Introduction
	Cdc37 in the Chaperoning of Protein Kinase
	Structure and Interaction
	Cdc37 in Cell Proliferation and Cancer
	Cdc37 and Cancer Treatment
	Roles for Cdc37 in Autophagy and Protein Aggregation Disorders
	Conclusions
	References
Chapter 6: p23 and Aha1: Distinct Functions Promote Client Maturation
	The Conformational Cycle of Hsp90
	The Hsp90 Co-chaperone p23
		Discovery and Isoforms of p23
		The Structure of p23
		The Interaction of p23 with Hsp90
		p23 and Hsp90 Client Maturation
		Hsp90-Independent Functions of p23
			The Intrinsic Chaperone Function of p23
			The Nuclear Function of p23
		Concluding Remarks
	The Hsp90 Co-chaperone Aha1
		Discovery and Isoforms of Aha1
		The Structure of Aha1
		The Interaction of Aha1 with Hsp90
		Aha1 and Hsp90 Client Maturation
	Integration of Aha1 and p23 into the Hsp90 ATPase Cycle
	Conclusion
	References
Chapter 7: Beyond Chaperoning: UCS Proteins Emerge as Regulators of Myosin-Mediated Cellular Processes
	Introduction
	UCS Proteins Are Indispensable for Myosin Folding but not Hsp90
	Structural Organization and Versatility of UCS Proteins as Myosin Chaperones
	UNC-45 Regulates Myosin Expression, Folding, Assembly, Contractile Function, and Degradation
	UNC-45 Proteins in Invertebrates
	UNC-45 Proteins in Vertebrates
	UCS Proteins in Yeasts, Fungi, and Apicomplexans
	UNC-45 and Cancers
	Conclusions and Future Work
	References
Chapter 8: Chaperonin: Co-chaperonin Interactions
	Introduction
	Activities of the E. coli GroEL/GroES Folding Machine
		Structure of GroEL and GroES
		The Role of GroES in the Reaction Cycle
	Roles of Bacterial Chaperonins
		Specific Functions of Bacterial Co-chaperonins
	Roles of Eukaryotic Group I Chaperonins
		Specific Functions of Eukaryotic Group I Co-chaperonins
	Conclusion
	References
Chapter 9: Co-chaperones of the Human Endoplasmic Reticulum: An Update
	Introduction
	The Chaperone Network of the Mammalian ER
	The Hsp70/Hsp40 Chaperone Network of the Mammalian ER
		The Two Hsp70s and NEFs of the Mammalian ER
		The Functional Cycle of BiP
		The Co-chaperones of BiP in the Mammalian ER
	The Dual Role of BiP and Its Co-chaperone Sec63 in Protein Import into the ER as an Example of Chaperone/Co-chaperone Action i...
		BiP Can Support Opening of the Human Sec61 Channel for ER Protein Import
		BiP Can Support ER Protein Import by Acting as a Molecular Ratchet on the Incoming Precursor Polypeptide
	Closing of the Human Sec61 Channel for Preservation of Cellular Calcium Homeostasis
	Not All Hsp70s Are Created Equal: BiP and Kar2p Cannot Substitute for Each Other in Sec61 Channel Gating
	Regulatory Mechanisms for the ER-Resident Hsp70/Hsp40 Chaperone Network
	Nucleotide Transport Into and Out of the ER
	Human Diseases Related to ER Chaperones or the Sec61 Channel: On Chaperonopathies and Sec61-Channelopathies
	Conclusions and Open Questions
	References
Chapter 10: J-Domain Proteins Orchestrate the Multifunctionality of Hsp70s in Mitochondria: Insights from Mechanistic and Evol...
	Introduction
	The Mitochondrial Hsp70 - Client Polypeptide Binding Cycle
	Mdj1: Multifunctional JDP that Evolved Mitochondria-Specific Functions
	Pam18: Specialized JDP that Functions in Protein Import
	Hsc20: Specialized JDP that Functions in Iron-Sulfur Cluster Biogenesis
	Evolutionary Dynamics of Mitochondrial JDP/Hsp70 Systems
	Concluding Remarks
	References
Chapter 11: Impact of Co-chaperones and Posttranslational Modifications Toward Hsp90 Drug Sensitivity
	Introduction
	The Chaperone Cycle
	Canonical Co-chaperones
		Hsp70/Hsp90-Organizing Protein (HOP)
		Cell Division Cycle 37 (Cdc37)
		Protein Phosphatase 5 (PP5)
		Activator of Hsp90 ATPase 1 (Aha1)
		Prostaglandin E Synthase 3 (p23)
		Immunophilins
		SGTA
		Sgt1
		C-Terminus of Hsc70-Interacting Protein (CHIP)
	New Co-chaperones
		Folliculin-Interacting Proteins 1 and 2 (FNIP1/2)
		Tuberous Sclerosis Complex 1 (Tsc1)
		TIMP-2
	Concluding Remarks
	References
Chapter 12: CHIP: A Co-chaperone for Degradation by the Proteasome and Lysosome
	Introduction to Molecular Chaperones and Protein Degradation
	Protein Degradation via the Proteasome
	Protein Degradation via Autophagy and the Lysosome
	The Carboxyl Terminus of Hsp70-Interacting Protein (CHIP)
	Structure of CHIP
	Interaction of CHIP with Chaperones and E2 Ligases
	CHIP Substrates and Human Disease
	Hsp70 and Hsp90: To Degrade or to Refold?
	Conclusions
	References
Chapter 13: HSP70-HSP90 Chaperone Networking in Protein-Misfolding Disease
	Introduction
	The HSP70 Chaperone Machine
	The HSP90 Chaperone Machine
	Major Co-chaperones Involved in Both HSP90 and HSP70 Complexes
	Disruption of Proteostasis and Disease
	Cooperation of HSP70 and HSP90 Chaperone Machines and Maintenance of Proteostasis in Neurodegenerative Disease
	Conclusions
	References
Index