Cell Biology

Sidelining Quality Control

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Science  29 Apr 2005:
Vol. 308, Issue 5722, pp. 603
DOI: 10.1126/science.308.5722.603a

Quality control within the endoplasmic reticulum has long been regarded as a mechanism that prevents the secretion of misfolded proteins: Endoplasmic reticulum-associated degradation (ERAD) and the inability of incorrectly folded proteins to access the export machinery are its key factors. However, in some cases, quality-control mechanisms fail, and misfolded or misassembled proteins are secreted and cause disease. One class of such diseases is known as the familial amyloidoses, in which aberrant forms of the protein transthyretin are secreted, become misfolded, and form pathological aggregates.

Sekijima et al. have examined the thermodynamics and kinetics of the folding and assembly of disease-associated forms of transthyretin. The endoplasmic reticulum is the entry site of the protein secretory pathway, and export from this compartment allows aberrant or misfolded proteins to transit to the Golgi and beyond. For many mutant forms of transthyretin, the balance between endoplasmic reticulum-assisted folding (ERAF) and ERAD determines the overall performance of this gatekeeping stage, and some cell types can actually secrete aberrant transthyretin efficiently. The competition between these intracompartmental pathways defines the ability of a particular type of cell or tissue to restrict or permit the secretion of aberrant proteins, and thereby determines the tissue selectivity and severity of protein-folding disorders. — SMH

Cell121, 73 (2005).

J. Am. Chem. Soc. 10.1021/ja0315154 (2004).

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