Walking Along the Serendipitous Path of Discovery

Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143-2200, USA.
Molecular biology of the cell (Impact Factor: 4.47). 01/2010; 21(1):15-7. DOI: 10.1091/mbc.E09-08-0662
Source: PubMed


Deciphering of the molecular mechanism of the "unfolded protein response" (UPR) provides a wonderful example of how serendipity can shape scientific discovery. Secretory and membrane proteins begin their journey to the cell surface in the endoplasmic reticulum (ER). Before leaving the organelle, proteins are quality-controlled, and only properly folded proteins are transported onwards. The UPR detects an insufficiency in the protein-folding capacity in the ER and in the ways of a finely tuned homeostat adjusts organelle abundance according to need. If the protein-folding defect in the ER cannot be corrected, the UPR switches from a cell-protective to a cell-destructive mode and activates apoptosis in metazoan cells. Such life or death decisions position the UPR in the center of numerous pathologies, including viral infection, protein-folding diseases, diabetes, and cancer. The UPR proved to be a rich field for serendipitous discovery because the molecular machines that transmit information about insufficient protein folding and activate appropriate gene expression programs function in unusual, unprecedented ways. A key regulatory switch in the UPR, for example, is a cytoplasmic, nonconventional mRNA spicing reaction, initiated by a bifunctional transmembrane kinase/endoribonuclease.

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    • "Oligomerization of the kinase, which is highly cooperative with respect to ATP levels, leads to activation of an RNAse domain and the cytoplasmic processing of an mRNA precursor encoding a transcription factor that triggers UPR. Identifying the components of this pathway and the mechanisms governing it required genetics, systems biology, biochemistry , chemical biology, structural biology, and, as recently recounted in Walter's E.B. Wilson Award Lecture, serendipity (Walter, 2010). Linking this pathway to cellular structure and organization, Walter described his lab's recent use of "
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