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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    ABSTRACT: A symposium was held at the University of California, San Diego, to honor the contributions of Nobel Laureate, George Palade, to cell biology. The speakers included Günter Blobel, on the structure and function of nuclear pore complexes; Peter Walter, on the unfolded protein response in health and disease; Randy Schekman, on human disease-linked mutations in the COPII machinery; Scott Emr, on the regulation of plasma membrane composition by selective endocytosis; Roger Kornberg, on the structure and function of the transcription machinery; Peter Novick, on the regulation of rab GTPases along the secretory pathway; Jim Spudich, on the mechanism of the enigmatic myosin VI motor; and Joe Goldstein, on the function of the Niemann-Pick C (NPC)-linked gene products, NPC1 and NPC2, in cholesterol transport. Their work showcased the multidisciplinary nature, diversity, and vitality of cell biology. In the words of George Palade, their talks also illustrated "how cell biology could be used to understand disease and how disease could be used to discover normal cell biology." An integrated understanding of the cellular machinery will be essential in tackling the plethora of questions and challenges posed by completion of the human genome and for understanding the molecular mechanisms underlying human disease.
    Molecular biology of the cell 07/2010; 21(14):2367-70. DOI:10.1091/mbc.E10-03-0179 · 4.47 Impact Factor
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    The Journal of Cell Biology 04/2011; 193(1):4-5. DOI:10.1083/jcb.1931pi · 9.83 Impact Factor
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