Coordinated Nonvectorial Folding in a Newly Synthesized Multidomain Protein

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Science  20 Dec 2002:
Vol. 298, Issue 5602, pp. 2401-2403
DOI: 10.1126/science.1078376

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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.

  • * Present address: Biological Sciences, Stanford University, 325 Serra Mall, Stanford, CA 94305, USA.

  • To whom correspondence should be addressed. E-mail: i.braakman{at}

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