scholarly journals Hsp70 molecular chaperones: multifunctional allosteric holding and unfolding machines

2019 ◽  
Vol 476 (11) ◽  
pp. 1653-1677 ◽  
Author(s):  
Eugenia M. Clerico ◽  
Wenli Meng ◽  
Alexandra Pozhidaeva ◽  
Karishma Bhasne ◽  
Constantine Petridis ◽  
...  
Keyword(s):  
Molecular Chaperones ◽  
Protein Homeostasis ◽  
Nucleotide Exchange ◽  
Cellular Functions ◽  
The Past ◽  
Hsp70 Family ◽  
Nucleotide Exchange Factors ◽  
Client Proteins ◽  
Structural Insights ◽  
Insight Into

AbstractThe Hsp70 family of chaperones works with its co-chaperones, the nucleotide exchange factors and J-domain proteins, to facilitate a multitude of cellular functions. Central players in protein homeostasis, these jacks-of-many-trades are utilized in a variety of ways because of their ability to bind with selective promiscuity to regions of their client proteins that are exposed when the client is unfolded, either fully or partially, or visits a conformational state that exposes the binding region in a regulated manner. The key to Hsp70 functions is that their substrate binding is transient and allosterically cycles in a nucleotide-dependent fashion between high- and low-affinity states. In the past few years, structural insights into the molecular mechanism of this allosterically regulated binding have emerged and provided deep insight into the deceptively simple Hsp70 molecular machine that is so widely harnessed by nature for diverse cellular functions. In this review, these structural insights are discussed to give a picture of the current understanding of how Hsp70 chaperones work.

scholarly journals The Link That Binds: The Linker of Hsp70 as a Helm of the Protein’s Function

Biomolecules ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 543 ◽  
Author(s):  
Chakafana ◽  
Zininga ◽  
Shonhai
Keyword(s):  
Protein Aggregation ◽  
Molecular Chaperones ◽  
Atp Hydrolysis ◽  
Sequence Data ◽  
Substrate Binding ◽  
Binding Domain ◽  
Nucleotide Exchange ◽  
Hsp70 Family ◽  
Nucleotide Exchange Factors ◽  
Functional Features

The heat shock 70 (Hsp70) family of molecular chaperones plays a central role in maintaining cellular proteostasis. Structurally, Hsp70s are composed of an N-terminal nucleotide binding domain (NBD) which exhibits ATPase activity, and a C-terminal substrate binding domain (SBD). The binding of ATP at the NBD and its subsequent hydrolysis influences the substrate binding affinity of the SBD through allostery. Similarly, peptide binding at the C-terminal SBD stimulates ATP hydrolysis by the N-terminal NBD. Interdomain communication between the NBD and SBD is facilitated by a conserved linker segment. Hsp70s form two main subgroups. Canonical Hsp70 members generally suppress protein aggregation and are also capable of refolding misfolded proteins. Hsp110 members are characterized by an extended lid segment and their function tends to be largely restricted to suppression of protein aggregation. In addition, the latter serve as nucleotide exchange factors (NEFs) of canonical Hsp70s. The linker of the Hsp110 family is less conserved compared to that of the canonical Hsp70 group. In addition, the linker plays a crucial role in defining the functional features of these two groups of Hsp70. Generally, the linker of Hsp70 is quite small and varies in size from seven to thirteen residues. Due to its small size, any sequence variation that Hsp70 exhibits in this motif has a major and unique influence on the function of the protein. Based on sequence data, we observed that canonical Hsp70s possess a linker that is distinct from similar segments present in Hsp110 proteins. In addition, Hsp110 linker motifs from various genera are distinct suggesting that their unique features regulate the flexibility with which the NBD and SBD of these proteins communicate via allostery. The Hsp70 linker modulates various structure-function features of Hsp70 such as its global conformation, affinity for peptide substrate and interaction with co-chaperones. The current review discusses how the unique features of the Hsp70 linker accounts for the functional specialization of this group of molecular chaperones.

scholarly journals Mechanisms of the Hsp70 chaperone systemThis paper is one of a selection of papers published in this special issue entitled “Canadian Society of Biochemistry, Molecular & Cellular Biology 52nd Annual Meeting — Protein Folding: Principles and Diseases” and has undergone the Journal's usual peer review process.

2010 ◽  
Vol 88 (2) ◽  
pp. 291-300 ◽  
Author(s):  
Jason C. Young
Keyword(s):  
Atp Hydrolysis ◽  
Peer Review Process ◽  
Nucleotide Exchange ◽  
Cellular Functions ◽  
Hsp70 Family ◽  
Nucleotide Exchange Factors ◽  
Hsp70 Chaperone ◽  
Hydrolysis Of ◽  
Selection Of

Molecular chaperones of the Hsp70 family have diverse functions in cells. They assist the folding of newly synthesized and stress-denatured proteins, as well as the import of proteins into organelles, and the dissociation of aggregated proteins. The well-conserved Hsp70 chaperones are ATP dependent: binding and hydrolysis of ATP regulates their interactions with unfolded polypeptide substrates, and ATPase cycling is necessary for their function. All cellular functions of Hsp70 chaperones use the same mechanism of ATP-driven polypeptide binding and release. The Hsp40 co-chaperones stimulate ATP hydrolysis by Hsp70 and the type 1 Hsp40 proteins are conserved from Escherichia coli to humans. Various nucleotide exchange factors also promote the Hsp70 ATPase cycle. Recent advances have added to our understanding of the Hsp70 mechanism at a molecular level.

scholarly journals Role of the HSP70 Co-Chaperone SIL1 in Health and Disease

2021 ◽  
Vol 22 (4) ◽  
pp. 1564
Author(s):  
Viraj P. Ichhaporia ◽  
Linda M. Hendershot
Keyword(s):  
Molecular Mechanisms ◽  
Three Dimensional ◽  
Dependent Manner ◽  
Nucleotide Exchange ◽  
Multisystem Disorder ◽  
Nucleotide Exchange Factors ◽  
Precise Understanding ◽  
Health And Disease ◽  
Client Proteins ◽  
Er Homeostasis

Cell surface and secreted proteins provide essential functions for multicellular life. They enter the endoplasmic reticulum (ER) lumen co-translationally, where they mature and fold into their complex three-dimensional structures. The ER is populated with a host of molecular chaperones, associated co-factors, and enzymes that assist and stabilize folded states. Together, they ensure that nascent proteins mature properly or, if this process fails, target them for degradation. BiP, the ER HSP70 chaperone, interacts with unfolded client proteins in a nucleotide-dependent manner, which is tightly regulated by eight DnaJ-type proteins and two nucleotide exchange factors (NEFs), SIL1 and GRP170. Loss of SIL1′s function is the leading cause of Marinesco-Sjögren syndrome (MSS), an autosomal recessive, multisystem disorder. The development of animal models has provided insights into SIL1′s functions and MSS-associated pathologies. This review provides an in-depth update on the current understanding of the molecular mechanisms underlying SIL1′s NEF activity and its role in maintaining ER homeostasis and normal physiology. A precise understanding of the underlying molecular mechanisms associated with the loss of SIL1 may allow for the development of new pharmacological approaches to treat MSS.

scholarly journals Integration of Rap1 and Calcium Signaling

2020 ◽  
Vol 21 (5) ◽  
pp. 1616 ◽  
Author(s):  
Ramoji Kosuru ◽  
Magdalena Chrzanowska
Keyword(s):  
Intracellular Signaling ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Nucleotide Exchange ◽  
Cellular Functions ◽  
Cellular Processes ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Gtpase Activating Proteins ◽  
Cardiac Excitation

Ca2+ is a universal intracellular signal. The modulation of cytoplasmic Ca2+ concentration regulates a plethora of cellular processes, such as: synaptic plasticity, neuronal survival, chemotaxis of immune cells, platelet aggregation, vasodilation, and cardiac excitation–contraction coupling. Rap1 GTPases are ubiquitously expressed binary switches that alternate between active and inactive states and are regulated by diverse families of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Active Rap1 couples extracellular stimulation with intracellular signaling through secondary messengers—cyclic adenosine monophosphate (cAMP), Ca2+, and diacylglycerol (DAG). Much evidence indicates that Rap1 signaling intersects with Ca2+ signaling pathways to control the important cellular functions of platelet activation or neuronal plasticity. Rap1 acts as an effector of Ca2+ signaling when activated by mechanisms involving Ca2+ and DAG-activated (CalDAG-) GEFs. Conversely, activated by other GEFs, such as cAMP-dependent GEF Epac, Rap1 controls cytoplasmic Ca2+ levels. It does so by regulating the activity of Ca2+ signaling proteins such as sarcoendoplasmic reticulum Ca2+-ATPase (SERCA). In this review, we focus on the physiological significance of the links between Rap1 and Ca2+ signaling and emphasize the molecular interactions that may offer new targets for the therapy of Alzheimer’s disease, hypertension, and atherosclerosis, among other diseases.

scholarly journals HSP90 Molecular Chaperones, Metabolic Rewiring, and Epigenetics: Impact on Tumor Progression and Perspective for Anticancer Therapy

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 532 ◽  
Author(s):  
Valentina Condelli ◽  
Fabiana Crispo ◽  
Michele Pietrafesa ◽  
Giacomo Lettini ◽  
Danilo Swann Matassa ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Molecular Chaperones ◽  
Heat Shock Protein 90 ◽  
Anticancer Therapy ◽  
Cellular Functions ◽  
Master Regulators ◽  
Cellular Processes ◽  
Direct Binding ◽  
Client Proteins ◽  
The Relationship

Heat shock protein 90 (HSP90) molecular chaperones are a family of ubiquitous proteins participating in several cellular functions through the regulation of folding and/or assembly of large multiprotein complexes and client proteins. Thus, HSP90s chaperones are, directly or indirectly, master regulators of a variety of cellular processes, such as adaptation to stress, cell proliferation, motility, angiogenesis, and signal transduction. In recent years, it has been proposed that HSP90s play a crucial role in carcinogenesis as regulators of genotype-to-phenotype interplay. Indeed, HSP90 chaperones control metabolic rewiring, a hallmark of cancer cells, and influence the transcription of several of the key-genes responsible for tumorigenesis and cancer progression, through either direct binding to chromatin or through the quality control of transcription factors and epigenetic effectors. In this review, we will revise evidence suggesting how this interplay between epigenetics and metabolism may affect oncogenesis. We will examine the effect of metabolic rewiring on the accumulation of specific metabolites, and the changes in the availability of epigenetic co-factors and how this process can be controlled by HSP90 molecular chaperones. Understanding deeply the relationship between epigenetic and metabolism could disclose novel therapeutic scenarios that may lead to improvements in cancer treatment.

scholarly journals Function of the N-terminus of zizimin1: autoinhibition and membrane targeting

2007 ◽  
Vol 409 (2) ◽  
pp. 525-533 ◽  
Author(s):  
Nahum Meller ◽  
M. Jody Westbrook ◽  
John D. Shannon ◽  
Chittibabu Guda ◽  
Martin A. Schwartz
Keyword(s):  
Limited Proteolysis ◽  
Small Gtpases ◽  
Guanine Nucleotide Exchange Factors ◽  
Pleckstrin Homology Domain ◽  
Membrane Targeting ◽  
Nucleotide Exchange ◽  
Rho Proteins ◽  
Cellular Functions ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors

Rho family small GTPases are critical regulators of multiple cellular functions. Dbl-homology-domain-containing proteins are the classical GEFs (guanine nucleotide exchange factors) responsible for activation of Rho proteins. Zizimin1 is a Cdc42-specific GEF that belongs to a second family of mammalian Rho-GEFs, CZH [CDM (Ced-5/DOCK180/Myoblast city)-zizimin homology] proteins, which possess a novel type of GEF domain. CZH proteins can be divided into a subfamily related to DOCK 180 and a subfamily related to zizimin1. The two groups share two conserved regions named the CZH1 (or DHR1) domain and the CZH2 (DHR2 or DOCKER) domains, the latter exhibiting GEF activity. We now show that limited proteolysis of zizimin1 suggests the existence of structural domains that do not correspond to those identified on the basis of homologies. We demonstrate that the N-terminal half binds to the GEF domain through three distinct areas, including the CZH1, to inhibit the interaction with Cdc42. The N-terminal PH (pleckstrin homology) domain binds phosphoinositides and mediates zizimin1 membrane targeting. These results define two novel functions for the N-terminal region of zizimin1.

scholarly journals Molecular chaperones and their denaturing effect on client proteins

2020 ◽  
Author(s):  
Sebastian Hiller
Keyword(s):  
Molecular Chaperone ◽  
Molecular Chaperones ◽  
Backbone Dynamics ◽  
Future Research ◽  
Chaperone Function ◽  
Structure And Dynamics ◽  
Client Proteins ◽  
Biophysical Techniques ◽  
Nmr Methods ◽  
Insight Into

Abstract Advanced NMR methods combined with biophysical techniques have recently provided unprecedented insight into structure and dynamics of molecular chaperones and their interaction with client proteins. These studies showed that several molecular chaperones are able to dissolve aggregation-prone polypeptides in aqueous solution. Furthermore, chaperone-bound clients often feature fluid-like backbone dynamics and chaperones have a denaturing effect on clients. Interestingly, these effects that chaperones have on client proteins resemble the effects of known chaotropic substances. Following this analogy, chaotropicity could be a fruitful concept to describe, quantify and rationalize molecular chaperone function. In addition, the observations raise the possibility that at least some molecular chaperones might share functional similarities with chaotropes. We discuss these concepts and outline future research in this direction.

scholarly journals The role of Rac in tumor susceptibility and disease progression: from biochemistry to the clinic

2018 ◽  
Vol 46 (4) ◽  
pp. 1003-1012 ◽  
Author(s):  
Victoria Casado-Medrano ◽  
Martin J. Baker ◽  
Cynthia Lopez-Haber ◽  
Mariana Cooke ◽  
Shaofei Wang ◽  
...  
Keyword(s):  
Rho Gtpases ◽  
Human Cancer ◽  
Intracellular Localization ◽  
Dynamic Control ◽  
Cancer Therapeutics ◽  
Nucleotide Exchange ◽  
Cellular Functions ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Cytoskeleton Reorganization

The family of Rho GTPases are involved in the dynamic control of cytoskeleton reorganization and other fundamental cellular functions, including growth, motility, and survival. Rac1, one of the best characterized Rho GTPases, is an established effector of receptors and an important node in signaling networks crucial for tumorigenesis and metastasis. Rac1 hyperactivation is common in human cancer and could be the consequence of overexpression, abnormal upstream inputs, deregulated degradation, and/or anomalous intracellular localization. More recently, cancer-associated gain-of-function mutations in Rac1 have been identified which contribute to tumor phenotypes and confer resistance to targeted therapies. Deregulated expression/activity of Rac guanine nucleotide exchange factors responsible for Rac activation has been largely associated with a metastatic phenotype and drug resistance. Translating our extensive knowledge in Rac pathway biochemistry into a clinical setting still remains a major challenge; nonetheless, remarkable opportunities for cancer therapeutics arise from promising lead compounds targeting Rac and its effectors.

scholarly journals The Hsp70-Chaperone Machines in Bacteria

2021 ◽  
Vol 8 ◽  
Author(s):  
Matthias P. Mayer
Keyword(s):  
Protein Quality ◽  
Cellular Protein ◽  
Sequence Motifs ◽  
Nucleotide Exchange ◽  
Surveillance Network ◽  
Nucleotide Exchange Factors ◽  
Hsp70 Chaperone ◽  
Range Of Functions ◽  
Client Proteins ◽  
Control Circuits

The ATP-dependent Hsp70s are evolutionary conserved molecular chaperones that constitute central hubs of the cellular protein quality surveillance network. None of the other main chaperone families (Tig, GroELS, HtpG, IbpA/B, ClpB) have been assigned with a comparable range of functions. Through a multitude of functions Hsp70s are involved in many cellular control circuits for maintaining protein homeostasis and have been recognized as key factors for cell survival. Three mechanistic properties of Hsp70s are the basis for their high versatility. First, Hsp70s bind to short degenerate sequence motifs within their client proteins. Second, Hsp70 chaperones switch in a nucleotide-controlled manner between a state of low affinity for client proteins and a state of high affinity for clients. Third, Hsp70s are targeted to their clients by a large number of cochaperones of the J-domain protein (JDP) family and the lifetime of the Hsp70-client complex is regulated by nucleotide exchange factors (NEF). In this review I will discuss advances in the understanding of the molecular mechanism of the Hsp70 chaperone machinery focusing mostly on the bacterial Hsp70 DnaK and will compare the two other prokaryotic Hsp70s HscA and HscC with DnaK.

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