[PDF][PDF] Cellular defenses against unfolded proteins: a cell biologist thinks about neurodegenerative diseases

MY Sherman, AL Goldberg - Neuron, 2001 - cell.com
MY Sherman, AL Goldberg
Neuron, 2001cell.com
A continuous threat to cell function and viability is the contain components of the ubiquitin-
proteasome degraaccumulation in cells of proteins with highly abnormal dative pathway and
also molecular chaperones, which conformations. Protein structures, once formed, are not
represent the two main systems that protect eukaryotic very stable chemical entities, and at
37 C, in the highly cells against the buildup of unfolded polypeptides. reactive environment
of the cell, spontaneous denatur-Exposure of cells to increased temperatures (eg, a ation …
A continuous threat to cell function and viability is the contain components of the ubiquitin-proteasome degraaccumulation in cells of proteins with highly abnormal dative pathway and also molecular chaperones, which conformations. Protein structures, once formed, are not represent the two main systems that protect eukaryotic very stable chemical entities, and at 37 C, in the highly cells against the buildup of unfolded polypeptides. reactive environment of the cell, spontaneous denatur-Exposure of cells to increased temperatures (eg, a ation and chemical modifications of proteins (eg, shift from 37 C to 42 C), oxygen radicals, heavy metals, through oxidation, isomerization, or glycation) must be or certain antibiotics may seem to represent quite difoccurring continuously. The rate of such damage to cell ferent challenges for a cell, but, in fact, they share the proteins can increase markedly upon exposure of cells capacity to cause severe damage to proteins. It is not surto harsh environmental conditions, such as increased prising, therefore, that common mechanisms emerged temperatures, oxygenfreeradicals, orheavymetals (esearly in evolution that enable cells to better withstand pecially mercury). Polypeptides with highly abnormal these diverse physical and chemical insults. Virtually all conformations may also result from mutations that precells respond to these potentially toxic conditions by vent normal folding or prevent the association of a polyinduction of a set of highly conserved genes that encode peptide with other subunits or stabilizing cofactors. Beheat shock proteins (Hsps). This set of proteins functions cause an accumulation of unfolded proteins can have as the major cellular defense against the accumulation very deleterious effects on cell function, all cells expend of damaged or mutant proteins. Among the Hsps in a significant fraction of their basal energy production to eukaryotic cells are many molecular chaperones, which ensure that proteins are accurately expressed, correctly function to retard protein denaturation and aggregation, folded, and targeted to the correct compartment. If naseveral antioxidant enzymes, which reduce oxidative tiveconformationsarelostthroughmutationorpostsyndamage to cell proteins, and components of the ubiquithetic damage, cells have elaborate mechanisms to pretin-proteasome pathway (Seufert and Jentsch, 1990; venttheaggregationoftheunfoldedmolecules, torefold Sommer and Seufert, 1992; Watt and Piper, 1997), which them, and if not possible, to hydrolyze the abnormal catalyze the selective degradation of abnormal polypeppolypeptides back to amino acids (Table 1). These protides in the nucleus and cytosol (Hershko and Ciechatective systems appear of particular medical interest nover, 1998; Schwartz and Ciechanover, 1999). since an accumulation of unfolded polypeptides in the nucleus or cytosol can disturb normal cellular functions and trigger apoptosis. The purpose of this essay is to Molecular Chaperones and the Repair review recent discoveries concerning the mechanisms of Damaged Proteins that protect cells against such an accumulation of ab-One large group of heat shock proteins functions as normal proteins and to discuss how these mechanisms molecular chaperones, including members of the Hsp70, are likely to be important in the nervous system in pro-Hsp90, Hsp104, Hsp40 (DnaJ), and small Hsp (Hsp27,
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