Chemistry of Life

Molecular genetics, biochemistry

cellular stress response

Just as cells repair DNA, they must also maintain the proteome by managing damaged proteins.

Heat stress denaturates (distorts) proteins, causing weakening of polar bonds, unfolding, and exposure of hydrophobic groups. Stress beyond the cell's tolerance will induce cell death. The cellular stress response (heat-shock response) protects organisms from damage resulting from environmental stressors such as heat, UV light, trace metals, and xenobiotics. Stress genes are activated to rapidly synthesize stress proteins, which are highly conserved in biological evolution and play similar roles in organisms from bacteria to humans.

In the living cell under non-stressed conditions, non-productive protein folding is in many, if not most, cases prevented by the action of a highly conserved set of proteins termed molecular chaperones. The major chaperone classes are hsp60 (including TCP1), hsp70 (stress70) and hsp90 (stress90), where hsp signifies 'heat-shock protein'. Normally, several key constitutive stress proteins are present at low levels to function as molecular chaperones, so as to facilitate folding, assembly, and distribution of newly synthesized proteins. Molecular chaperones interact with unfolded or partially folded protein subunits, such as nascent chains emerging from the ribosome or extended chains undergoing translocation across subcellular membranes. The chief function of chaperones is prevention of inappropriate association or aggregation of exposed hydrophobic surfaces by directing their substrates into productive folding, transport, or degradation pathways. Chaperones stabilize non-native conformation and facilitate correct folding of protein subunits, often coupling ATP binding/hydrolysis to the folding process. Chaperones do not interact with native proteins, nor do they form part of the final folded structures. Some chaperones are non-specific in that they interact with a wide variety of polypeptide chains, while other chaperoness are restricted to specific targets. Chaperones are essential for viability, so their expression is often increased by cellular stress.

Physical or chemical stress inactivates or down-regulates many genes, including many housekeeping genes, while up-regulating stress genes that perform orchestrated induction of key proteins necessary for cellular protein repair and degradation systems. When an organism is environmentally stressed, stress proteins protect and repair vulnerable protein targets, and play a role in the proteasomal and ubiquitin protein degradation pathways (for removal of unsalvageable proteins) [diags. 1, 2, 3]. Stress proteins assist in the folding, translocation, and assembly of other proteins, so many stress proteins are also called molecular chaperones. However, not all stress proteins are chaperones and, conversely, not every molecular chaperone is a stress protein.

Dimeric hsp70 (stress70), is a large, multigene family with members located in subcellular compartments such as the cytoplasm, mitochondria, and endoplasmic reticulum. Hsp70 proteins, probably in association with heat-shock protein, hsp40 ensure correct folding of newly synthesized peptides by binding to the elongating peptide chain and maintaining it in a loosely folded state until synthesis is complete. In its ATP-bound state hsp70 has a low protein affinity but when the nucleotide is hydrolysed to give the ADP state the affinity is increased, so hsp70 disassociation is an ATP-dependent process that occurs as the protein folds into correct three-dimensional shape.

Proteins destined for distribution to subcellular compartments are maintained in their unfolded state and chaperoned to the destination compartment for translocation. Hsp70 binds its substrates in an extended conformation through hydrophobic interactions, retaining the unfolded state during transport. Within a destination organelle, the target protein then interacts with another member of the hsp70 family that performs folding functions.

Another heat-stress family, the chaperonins includes the chaperonin60 (cpn60, hsp60) family that is found in eubacteria, mitochondria, and plastids. Hsp60 (cpn60) is a large, tetradecameric protein with a central cavity, which is present in all biological compartments except the endoplasmic reticulum. Chaperonins assemble into large double donut-shaped complexes where the chaperonins interact with and globally enclose collapsed folding intermediates in the central cavity where efficient folding can proceed in a protected environment, ensuring higher-level folding and assembly of protein subunits into functional complexes. As in hsp70, the binding of ATP stimulates release of the substrate, and hydrolysis of ATP restores high binding affinity. It functions in conjunction with a co-protein, cpn10, which enhances its ability to eject proteins during the ATPase cycle. Chaperone proteins of the hsp90 class are found associated with inactive or unstable substrate proteins within the cell, thus preventing their aggregation and/or permitting rapid activation. A cytoplasmic functional homolog, TCP1 facilitates folding of actin and tubulin. This chaperonin family appears to be distantly related to the cpn60 group, though it is not considered a stress protein because its synthesis is not induced by stress.

Under environmental stress, dramatic changes occur in the hsp70 and cpn60 families, suggesting that they perform dual roles in protein protection and repair. Synthesis of hsp70 increases in response to stress, whereupon hsp70 protects the cell from stress-induced damage by binding to vulnerable proteins, preventing protein denaturation, and preventing the formation of insoluble aggregates. Hsp70 can also break up existing aggregates and repair proteins to constitutive biological activity, and hsp70 guides irreparably damaged proteins to the proteasome for degradation. Environmental stress also stimulates synthesis of cpn60 and induces it to prevent aggregation of misfolded proteins and to facilite renaturation and assembly into functional complexes. It is believed these functions enable stress proteins to confer stress tolerance by maintaining the integrity of proteins and protein complexes associated with critical physiological processes.

Thermophilic cell lines adapted for survival at high temperatures constitutively synthesize the stress protein hsp70 at high levels, whereas temperature-sensitive cell-lines do not. Several stress protein families, including hsp90, hsp70, chaperonin60, hsp40, the low molecular weight stress proteins, and ubiquitin, are expressed in diverse phyla. Studies comparing the stress protein repetoir of closely related species inhabiting different environments have demonstrated that differences in the heat-stress response are correlated with thermal resistance, suggesting that stress proteins help organisms adapt to harsh or unpredictable environments. [r]

: Stress genes, proteins, molecular chaperones : ubiquitin : proteasome :


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. . . transcription begun 10/06/06