Coordinated nonvectorial folding in a newly synthesized multidomain protein |
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Authors: | Jansens Annemieke van Duijn Esther Braakman Ineke |
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Institution: | Department of Bio-Organic Chemistry 1, Bijvoet Center for Biomolecular Research, University of Utrecht, Padualaan 8, 3584 CH Utrecht, Netherlands. |
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Abstract: | The low-density lipoprotein receptor (LDL-R) is a typical example of a multidomain protein, for which in vivo folding is assumed to occur vectorially from the amino terminus to the carboxyl terminus. Using a pulse-chase approach in intact cells, we found instead that newly synthesized LDL-R molecules folded by way of "collapsed" intermediates that contained non-native disulfide bonds between distant cysteines. The most amino-terminal domain acquired its native conformation late in folding instead of during synthesis. Thus, productive LDL-R folding in a cell is not vectorial but is mostly posttranslational, and involves transient long-range non-native disulfide bonds that are isomerized into native short-range cysteine pairs. |
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