Chaperones Of The Cellular Compartments

Molecular chaperones have been described across tissues and subcellular compartments (see Table 44.1 and Figure 44.1).

Cytoplasmic chaperones The HSP70 and HSP90 families are found mainly in the cytoplasmic compartment. Hsp90 and Hsp70 refold proteins in an ATP-dependent way, where Hsp90 is dedicated to specific substrates and Hsp70 refolds more general substrates (Young et al., 2004).

The super-family of mammalian small heat shock or stress proteins (sHsp) in humans consists of the known members HSP27, aB-crystallin, aA-crystallin, Hsp20,

HspB2, HspB3, and cvHsp. sHsp's have the ability to form supra-molecular structures, either homo-oligomeric or hetero-oligomeric complexes, ranging in molecular weight from 50 to 1000 kDa depending on the degree of stress. The basic structural units of sHsp complexes are dimers that are formed by interaction of segments of the a-crystallin domain. The sHsp's can bind and prevent aggregation of denatured proteins, but usually they cannot refold them. They may help target their substrate for proteolysis, or they may store it for subsequent refolding by the Hsp70 chaperone system (Laksanalamai et al., 2004).

Whereas unfolded cytoplasmic proteins evoke the heat shock response, other cellular organelles also can evoke appropriate protective mechanisms.

Chaperones of the endoplasmic reticulum During protein synthesis, nascent proteins are processed within the endoplasmic reticulum (ER), where a subset of chaperones and folding enzymes form multiprotein complexes. The lectins calnexin and calreticulin and the oxidoreductase Erp57 are involved in ER-quality control, which prevents aggregation and export along the secretory pathway of misfolded and incompletely assembled proteins. Appropriate folding of polypeptides requires chaperone proteins such as Bip/Grp78 and calreticulin. Overexpression of proteins or abnormally folded nascent proteins can lead to protein accumulation and aggregation in cells, causing ER stress, which in severe cases could trigger cell death. A cellular protective mechanism known as the unfolded protein response (UPR) evolved to induce the expression of various genes including molecular chaperones and to activate ER-associated protein degradation (ERAD). The ER-chaperones relay a signal that temporarily induces a general slow-down in cellular division to prioritize the expression of proteins required for the appropriate synthesis of the nascent protein. Cells with high secretory capacity such as the ones found in endocrine glands or immunoglobulin-producing cells often require high ER-chaperone usage. The 47-kDa heat shock protein 47 (HSP47) is an ER-resident, collagen-specific molecular chaperone that has been shown to play a major role during the processing and/or secretion of procollagen in, for example, fibroblasts (Miyaishi et al., 1995; Castro-Fernandez et al., 2005).

Mitochondrial chaperones Mitochondria contain several members of the major chaperone families that have important functions in maintaining this organelle's function. Changes in the energy status of the cells require adaptations in the protein import machinery such as the induction of cytosolic molecular chaperones that transport precursors to the matrix, the up-regulation of outer membrane import receptors, and the increase in matrix chaperonins (e.g., Hsp60) that facilitate the import and proper folding of the protein for subsequent compartmentation in

TABLE 44.1 Classes of molecular chaperones


Function and subcellular localization aA-crystallin aB-crystallin BBS6/MKKS Calnexin


Clusterin/XIP8/apo-J Erdj4/MDG1 GRP78 (BIP) Grp94/gp96 GRP170

Hsp20/25/27 HspB2, HSPB3, cvHsp Hsp40/Erdj1 -5/DnaJ

Bind unfolded proteins, interact with matching hsp70's

Hdjl: human dnaJ homologue abundant in neurons


Hsp56/FKBP59 Hsp60/Hsp10 Hsp70 family

Small hsp—Stabilization against aggregation during heat shock. Localization: Post-Golgi membranes Small hsp—Stabilization against aggregation during heat shock. Localization: Post-Golgi membranes McKusick-Kaufman syndrome—Homology to chaperonin

Interacts and assists with the folding of new proteins that carry monoglucosylated N-linked glycans; retains incompletely folded proteins in the ER. Localization: ER membrane

Folding of glycosylated proteins in the ER in coperation with glucosyltransferase; similar to calnexin. Localization: ER lumen

ERP29 endoplasmic reticulum protein 29. Localization: ER

DnaJ family member. Localization: ER

Ca2+-binding—Hsp70 family member. Localization: ER

Hsp90 ER luminal homolog—Possible role in the antigen presentation pathway. Localization: ER Localization: ER

Small hsp's—Stabilization against aggregation during heat shock. Localization: Multiple Stimulates BIP ATPase activity; binds nascent polypetides. Localization: ER

Processing and secretion of collagen. Localization: ER

FK506 binding protein 59 induced by cardiotrophin; cardiac hypertrophy. Localization: ER

Folding of imported proteins (known as chaperonins in bacteria). Localization: Mitochondria

ATP-dependent stabilization of hydrophobic regions in extended polypeptide segments; role in the ubiquitin-proteasome system; binding of nascent polypetides; maintains translocation-competent ER and mitochondrial precursor proteins in the cytosol Hsp72: stress inducible, Hsc73, binds to nascent chains, constitutive Mortalins mot-1, mot-2/mthsp70/GRP75

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