Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Heat Shock Protein (HSP)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101809

Synonyms

There are synonyms of each HSP members in mammals:  DNAJ: HSP40;  HSPA: HSP70;  HSPB: small HSP families;  Human chaperonin families: HSP60 and CCT;  HSPC: HSP90;  HSPH: HSP110 (Kampinga et al. 2009).

The cellular and species-specific isoforms are given in each part of the text.

Historical Background

Heat shock proteins (HSPs) were first described by Ritossa (1962) in Drosophila (Drosophila busckii and Drosophila melanogaster) in response to temperature, and the active genes coding HSPs are called puffs. Ritossa (1962) also showed increased expression of HSPs following 2,4-Dinitrophenol (DNP) treatment instead of temperature (Ritossa 1962). Later, Koninkx (1976) decided to analyze all inducing conditions of HSPs in Drosophila, so he studied several stress conditions on different tissues and finally reported that puffs could be detected under different stress conditions not only temperature changes. Koninkx (1976) also used the term “heat shock proteins” for puff patterns (Koninkx 1976).

HSPs are a conserved family through the evolution from bacteria to high eukaryotes, although the number of HSP members changes in different species. For example, while Escherichia coli have three HSP, human HSPs have 13 members. HSP nomenclature was updated in 2009 by Kampinga et al. According to this updated version, HSPs can be grouped as HSPH (HSP110), HSPC (HSP90), HSPA (HSP70), DNAJ (HSP40), HSPB (small HSP) families, and human chaperonin families (HSP60 and CCT) (Kampinga et al. 2009).

Regulation of HSPs

Factors that initiate the expression of HSPs are divided into three major categories: (1) environmental stress conditions such as heat shock or reactive oxygen species (ROS), (2) pathophysiological conditions such as ischemia, inflammation, or aging, and (3) cellular conditions, i.e., cell cycle and differentiation (Morimoto 1998). Transcription of HSPs starts with a stress condition, which induces the activation of heat shock factor (HSF) and in return activation of stress-induced transcription. Activated HSF binds to heat shock promoter element (HSE) which consists of a pentanucleotide motif 5′-nGAAn-3′ (Fernandes et al. 1994; Lis and Wu 1993; Lis and Wu 1993; Voellmy 1994; Wu 1995). HSF binding to HSE following inducing conditions causes chromatin remodeling and interaction between HSF and transcriptional machinery members (Morimoto 1998). Activation mechanisms of HSFs are shown in Fig. 1.
Heat Shock Protein (HSP), Fig. 1

Demonstration of HSF-1 cycle. The cells initiate transcription of heat shock elements (HSE) in response to cellular stress as increased oxidized molecules, heat stress, or other stress conditions. HSE transcription is initiated by heat shock factor (HSF). HSF monomers are located in cytosol as bounded to HSP90 in nonstress conditions. After the stress signal, HSP90 leaves from HSF-1 monomers; each monomer is phosphorylated and forms a HSF-1 trimer by binding to each other. HSF-1 trimer translocates into nucleus, binds to HSE sequence, and triggers the transcriptional activation of stress-related genes as heat shock proteins (HSPs). HSF-1 trimer separates from HSE sequence after HSP70 and HSP40 binding, migrates to cytosol back, and re-monomerizes

The Structure and Functions of HSPs

HSPs can be thought as the solutions of ancestor cells developed to deal with the problems of protein folding, cellular stress, and cell signaling. In this direction, HSPs have roles in several different functions. The number of HSP members and the roles of HSPs in cellular pathways increase in higher organisms. In this chapter, the structural patterns and the basic roles of HSP members are summarized.

HSP110 Family

Each member of HSP110 family has alternative names as HSPH1/HSP105, HSPH2/HSPH4/APG-2/HSP110, HSPH3/HSPH4L/APG-1, and HSPH4/HYOU1 in humans. HSPH members are co-chaperones of HSP70 and HSP90 members. HSPH family shows poor ATPase activity compared to HSP70 members, but they act as nucleotide exchange factors (NEFs) of HSP70 (HSPA) members both in mammalian and yeast. HSPH members interact with HSPA and assist exchange of ADP with ATP. HSPA-mediated folding escalates following ATP-HSPA binding (Shaner et al. 2008; Vos et al. 2008) (Fig. 2).
Heat Shock Protein (HSP), Fig. 2

The Hsp70 folding machinery cycle. HSP70 binds to nascent or misfolded proteins, client proteins, which are captured and presented by HSP40 molecules. HSP40 molecules help HSP70 to activate its own ATPase activity, and HSP70 can bind to client proteins with the conformational change caused by ATP hydrolysis. Then, nucleotide exchange factors (NEF) such as HSP110 provide ADP to ATP exchange and cause a second conformational change, open state, to release the client proteins. Client proteins are released as folded or misfolded and misfolded proteins can repeat this cycle several times for the proper folding

HSP110 family members can be found in cytosol, nucleus, and ER. Different from other members, HSPH3 is highly detected in testis during spermatogenesis. Expressions of HSPH1, 2, and 4 are ubiquitous (Vos et al. 2008). Yeast homologs of HSP110 family, Stress Seventy E (SSE) family, were shown to be related with cell wall integrity of yeast and morphogenesis (Shaner et al. 2008).

According to sequence and structure studies, HSP110 family was shown to be a divergent cognate of HSP70 family proteins. The nucleotide-binding domain and substrate-binding domains of HSP110 show likeliness with Dna70. Despite the structural similarity between HSP110 and HSP70, HSP110 tends to act like NEF instead of acting like HSP70 as performing ATP-dependent folding activity or holdase activity (Oh et al. 1999).

HSP90 Family

HSP90 proteins are found in bacteria and eukaryotes, but they do not exist in archaea. While there are several isotypes of HSP90 proteins in eukaryotes including ER- or mitochondria-specific HSP90 proteins, bacteria have HtpG, and this protein is not as essential as the ones in eukaryotes. The studies to explain the main role of HtpG proteins are still continuing (Versteeg et al. 1999). The main isoforms of mammalian HSP90 proteins are inducible cytoplasmic isoform HSP90α, constitutively expressed cytoplasmic isoform HSP90β, ER isoform GRP94, and mitochondrial matrix isoform Trap-1. Yeast has two isoforms of HSP90: Hsc82 and Hsp82 (Li and Buchner 2013).

HSP90 proteins have three main domains: the N-terminal domain (NTD) or adenine-nucleotide-binding (NBD) domain, the middle domain (MD), and C-terminal domain (CTD). The CTD executes the homo-dimerization of HSP90 monomers. NTD and MD are linked with a charged linker sequence, which is missing in bacterial HSP90. This charged linker sequence was reported to be involved in the modulation of activity in vivo (Jackson 2013). Except this charged linker sequence, the rest of the three domains are conserved throughout the evolution (Li and Buchner 2013). Another important sequence is located at the end of C-terminal, MEEVD sequence. MEEVD sequence was shown to interact with co-chaperones containing tetratricopeptide repeat (TPR) motives such as Hop, FKBP51/52, and CyP40 proteins (Jackson 2013). The structure of HSP90 dimers is summarized in Fig. 3.
Heat Shock Protein (HSP), Fig. 3

The structure of HSP90 monomer and dimer. HSP90 monomers have three main domains: the N-terminal domain (NTD) or adenine-nucleotide-binding (NBD) domain, the middle domain (MD), which is between NBD, and C-terminal domain (CTD). The CTD executes the homo-dimerization of HSP90 monomers. NTD and MD are linked with a charged linker sequence that is missing in bacterial HSP90

The interaction of client proteins with HSP90 either secures the proper folding or enables proper functioning. The client proteins may be protein kinases or steroid hormone receptors (SHRs) and are involved in crucial mechanisms including immune system and RNA modification. In addition to folding role of HSP90, its crucial role in protein degradation was also reported. HSP90 is involved in degradation of both hydrophilic proteins such as cytosolic proteins and hydrophobic proteins such as ER membrane proteins. HSP90 is also related to the proteasomal system. An E3 ubiquitin ligase protein, carboxyl-terminus of Hsp70-interacting protein (CHIP), interacts with both HSP70 and HSP90. Other reported E3 ligases interacting with HSP90 are Ubr1 and Cul5 (Li and Buchner 2013).

HSP70 Family

The gene coding for HSP70 homolog in Escherichia coli, DnaK, was first discovered by Costa Georgopoulos (Georgopoulos 1971). After its discovery, HSP70 family took overwhelming interest from many laboratories around the world. Investigations have shown that HSP70 performs weak ATPase activity alone and an increased ATPase activity in the presence of different protein and peptide substrates. Stimulation of HSP70 by protein and peptide substrates is conserved throughout the prokaryotes and eukaryotes (Zylicz and Wawrzynow 2001).

HSP70 consists of a 25-kDa carboxy-terminal, which performs substrate-binding activity, peptide-binding domain (PBD), and a 40-kDa amino terminal that carries out adenine nucleotide-binding activity, NBD, and also controls the conformation of PBD. PBD detects and binds 5-amino acid long hydrophobic regions of substrates (Kampinga and Craig 2010).

The substrate binding of HSP70 members occurs with the help of cofactors, HSP40 members or J proteins, since most of the members may have molecular weights different than 40 kDa. J proteins assist HSP70 members to hydrolyze ATP and bind client proteins. Afterward, releasing of substrate and recycling of bound nucleotide is performed with the assistance of NEFs (Kampinga and Craig 2010) (Fig. 2). One of the NEFs is HSP110 as mentioned in the previous section.

HSP70 proteins basically perform de novo protein folding. While 10–20% bacterial proteins are folded via HSP70 action, it is expected that more eukaryotic proteins be probably in need of HSP70 to be folded properly. The acquirement of HSP70 increases with higher protein sizes and stress conditions such as incorrectly synthesized nascent proteins, mutations, and environmental stress conditions. HSP70 proteins regulate cellular functions including homeostasis, differentiation, cell death, or survival. HSP70 and HSP90 proteins keep signaling regulators in their inactive form in the absence of signaling trigger but release them after signaling cascade is initiated. HSP70 proteins can also implement antiapoptotic effect via regulating caspases at different stages (Mayer and Bukau 2005). Another important role of HSP70 is its interaction with 19S regulatory particle of 26S proteasome. With this interaction HSP70 is involved in the association and dissociation of 26S proteasome and plays role in the degradation of oxidized proteins by proteasomal system (Grune et al. 2011).

Chaperonins (HSP60 and CCT)

Chaperonin proteins are in the molecular weight of ~60 kDa with low ATPase activity. Chaperonin proteins fall into two major groups: group I chaperonins and group II chaperonins (Valpuesta et al. 2002). The structures of group I and group II chaperonins are summarized with Fig. 4ac.
Heat Shock Protein (HSP), Fig. 4

The structure of group I and group II chaperonins. (a) GroEL (HSP60) and GroES (HSP10). (b) Top view of mammalian CCT. (c) A single α subunit of thermosomes. Group I chaperonin GroEL is composed of homodimers, which includes two heptameric rings. Each heptameric ring has three main domains as equatorial domain, apical domain, and intermediate domain. The co-chaperonin of GroEL, GroES (HSP10), is also a heptameric protein. The archaeal group II chaperonins are generally named as thermosomes. Eukaryotic cytosolic chaperonin containing TCP-1 (CCT or TRiC) is another group II chaperonin protein. CCT is also composed of two rings like other chaperonins, and each ring that constitutes CCT contains eight different subunits

The most important and studied example of group I chaperonins is GroEL protein (HSP60) of Escherichia coli. Group I chaperonins are found in bacteria and the endosymbiosis-originated organelles of eukaryotic cells as mitochondria and chloroplasts. GroEL is composed of homodimers, which includes two heptameric rings. Each heptameric ring has three main domains as equatorial domain, apical domain, and intermediate domain. The apical domain is responsible for binding of unfolded proteins, and equatorial domain performs ATP-binding activity and modulates inter- and intramolecular interactions. Intermediate domain holds the two domains together. There is also a co-chaperonin which is a heptameric protein that helps the group I chaperonins to perform their activities. The co-chaperonin of GroEL is called GroES (HSP10) in Escherichia coli (Ranson et al. 1998; Valpuesta et al. 2002).

Group II chaperonin proteins are found in archaea and in the cytoplasm of eukaryotes. In contrast to the group I chaperonins, group II chaperonins have little sequence homology, and their structural patterns are very heterogeneous. The archaeal chaperonins are generally named as thermosomes (Valpuesta et al. 2002). Group II chaperonins are also named as T-complex protein-1 (TCP-1) proteins (Ranson et al. 1998). One of the most important members of group II chaperonin proteins is eukaryotic cytosolic chaperonin containing TCP-1 (CCT or TRiC). CCT is also composed of two rings like other chaperonins, and each ring that constitutes CCT contains eight different subunits (α to θ; CCT1 to eight in yeast). According to previous studies, CCT protein was found to be encoded by a single gene in all organisms and tissues, but only in mammalian testis, ζ subunit is encoded by a tissue-specific gene (Ranson et al. 1998).

Both groups of chaperonins assist other proteins to be folded properly. In general, the interaction of GroEL protein with its unfolded substrate is nonspecific and based on the interaction between the apical domain and hydrophobic sides of unfolded proteins. The interaction of eukaryotic cytosolic CCT with its substrates such as actin or tubulin is based on subunit-specific interaction with substrates. In addition, actin and tubulin are the major substrates of CCT, and it interacts with 9–15% of newly synthesized proteins. CCT can interact with other cytoskeletal proteins, the proteins related with cell cycle such as cyclin E, phototransduction as Gα-transducin, some viral proteins, and Von Hippel-Lindau tumour suppressor protein (VHL). CCT was also reported to interact with other chaperones HSP70 and Hop (p60) (Valpuesta et al. 2002).

HSP40 Family

The crucial member of chaperone network is HSP70, which has inducible and constitutive forms in cells. Its interaction with its substrates and ATP hydrolysis for catalytic activity occur with the help of co-chaperones such as J proteins or DnaJ (HSP40) family (Kampinga and Craig 2010). The first reported activities of HSP40 family were its role in the replication of λ phage DNA via assisting ATP hydrolysis of bacterial DnaK. Different numbers of homologs of DnaJ proteins exist in different organisms such as six homologs in Escherichia coli, 22 homologs in Saccharomyces cerevisiae, and more than 20 homologs in mammalian cells (Qiu et al. 2006).

DnaJ proteins have three conserved regions in their structure: J domain, Gly/Phe-rich region, and the cysteine repeats. All members of this family have J domain, and this domain is located in the N-terminal in most of the members. According to presence of Gly/Phe-rich region, and the cysteine repeats, J proteins fall into three major groups. Type I J proteins have all of these three regions, type II J proteins have J domain and Gly/Phe-rich region, and type III J proteins have only J domain (Fig. 5). In addition to these conserved regions, there are also differential regions, which modify their functions in different species. There are tissue-specific DnaJ proteins in higher organisms, and also some DnaJ proteins are expressed in all tissues. DnaJ proteins can be found in all compartments of cells including ER, cytosol, and nucleus (Qiu et al. 2006).
Heat Shock Protein (HSP), Fig. 5

Schematic demonstration of type-I, II, and III J proteins. HSP40 family members or J proteins have three conserved regions: J domain, Gly/Phe-rich region, and the cysteine repeats. All members of this family have J domain, and most of the members have J domain at the N-terminal. According to presence of Gly/Phe-rich region, and the cysteine repeats, J proteins fall into three major groups: type I J proteins have all of these three regions, type II J proteins have only J domain and Gly/Phe-rich region, and type III J proteins have only J domain

The basic roles of DnaJ proteins are related to folding of newly synthesized proteins in ER, cytosol, and mitochondria and prevention of protein aggregate formation. In addition to its interaction with HSP70, it can also interact with HSP90. TPR2 member of DnaJ family is involved in substrate transfer between HSP90 and HSP70. DnaJ proteins are involved in ER stress response via regulating the activity of HSP70 homolog BiP. Over and above its co-chaperone activity in protein folding, DnaJ proteins can act like chaperones on their own and interact with unfolded or nascent proteins. Sis1 member of DnaJ family is related to the small subunit of ribosome and initiation of translation in yeast (Qiu et al. 2006).

Small HSP Family

The molecular mass of small heat shock proteins (sHSPs) ranges between 15 kDa and 30 kDa. Small HSPs are found in archaea, bacteria, and eukaryotes and can be detected in different tissues even with no stress factors (Jakob et al. 1993).

The first very characteristic feature of sHSPs is having α-crystallin domain, which has a very conserved sequence and located between N-terminal and C-terminal domains. It was suggested that there may be a middle domain between the N-terminal domain and α-crystallin domain; also there may be more than one α-crystallin domain in sHSPs (Fig. 6). sHSPs are called “small” because of their small monomeric molecular size, but on the other hand they tend to construct oligomeric large structures up to 200-kDa molecular size. sHSPs are stabilized by intermolecular interactions to form large oligomeric structures, and these intermolecular interactions can be made by terminal regions of the molecules (Hilton et al. 2013).
Heat Shock Protein (HSP), Fig. 6

Schematic demonstration of structure of sHSPs. sHSPs has α-crystallin domain which has a very conserved sequence and located between N-terminal and C-terminal domains. There may be also a middle domain between the N-terminal domain and α-crystallin domain; also there may be more than one α-crystallin domain in sHSPs

sHSPs family has plenty of members, and as expected from the number of members, sHSPs take part in many different cellular processes. First of all, like other members of HSP family, sHSPs are molecular chaperones, which prevent the aggregation of other proteins. Especially α-crystallin domain is responsible for preventing the aggregation of aggregation-prone proteins. When the native proteins transform into unfolded proteins with the effect of stress conditions such as heat, sHSPs bind and hold these proteins in unfolded state. sHSPs act in an ATP-independent manner. While HSP60, 70, and 90 tend to interact with unfolded proteins and fold them in an ATP-dependent manner, sHSPs show “holdase” activity. As sHSPs perform their holdase activity, they cannot operate the folding of the target proteins. For this reason, after binding to unfolded targets, the complex interacts with HSP70/HSP40 complex to fold the unfolded protein back with the help of nucleotide exchange factor HSP100. There are also studies showing that sHSPs are in relation with the proteasomal system and mitochondrial Lon proteases for degradation of unfolded proteins (Hilton et al. 2013).

HSP47

HSP47 is another protein, which responds to HSE. HSP47 can be listed in the group of proteins that respond to heat shock stress and act as molecular chaperone. HSP47 has sequence homology with serpin protein family so that the gene coding for this protein is named as SERPINH1 instead of HSP (Kampinga et al. 2009).

During the experiments with this protein family, different names were given to identified HSP47 family members in different organisms as gp46 in human and rats, Hsp47 in chicken, CB48 in bovine, and J6 in mice and also as colligin because of its affinity to collagen (Sauk et al. 2005). HSP47 is mainly involved in the correct folding of collagen and therefore has a crucial role for the functions of this protein.

HSPs in Diseases

Proper protein folding is crucial for cells to execute protein turnover, cell signaling, homeostasis, proliferation, and differentiation. On the other hand, mutations or stress conditions may cause impairment of protein folding so that folding machinery is crucial for dealing with stress, mutations, and aging. Here are just a few examples of HSP involvement in diseases.

With the aging population, studies on neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s disease became important to provide healthy aging conditions and to deal with high healthcare and treatment expenses. Protein quality control and protein degradation are two crucial systems for neural system. Especially HSP70 is very important for protein degradation with proteasomal system and HSC70 for chaperone-mediated autophagy. Proper protein folding is orchestrated with HSP system for preventing aggregations (Brown 2007).

Involvement or overexpression of HSPs has been reported for many human cancers, and HSPs were found to be related with cellular proliferation and differentiation; tumor invasion, metastasis, and the escape from immune recognition. The self-sufficiency of growing tumor cells is basically supported by HSP90. Rapid responses to extracellular matrix changes are also facilitated by HSP90 function. HSP90 and HSP70 are involved in transformation via binding to tumor suppressors such as p53 and Rb107. HSPs are also involved in the development of resistance against chemo- or radiotherapy. In these kinds of cancer therapies, simply cellular stress is aimed via oxidation of macromolecules such as lipids, proteins, and DNA. HSPs are involved in this part for the defense of cancer cells against this oxidative damage and help cancer cells to develop resistance against therapy (Calderwood et al. 2006).

Another example of diseases that HSPs are involved is atherosclerosis. Increased HSP70 activity and expression were shown in necrotic and lipid-accumulated thickened atheroma. While HSP70 increase was shown to be related to stress, HSP60 expression was shown to correlate positively with severity of atherosclerosis. Increase in oxLDL triggers the expression of HSP47, which regulates procollagen maturation and extracellular matrix formation (Xu 2002).

Concluding Remarks

Heat shock proteins are a family of proteins, which are synthesized as a response to stressful conditions. They mainly participate in the synthesis, folding, assembly, export, and turnover of proteins. HSPs are classified according to their molecular weights and play role in several different functions. Therefore they play crucial roles in the several diseases, which are known to be related to protein quality control and stress response. Among others, HSP60, 70, and 90 are the most widely studied ones. Regarding the involvement of HSPs in many different pathways, more studies are required to detail their interaction with other proteins.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Medical BiochemistryMarmara University School of MedicineMaltepe, IstanbulTurkey