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Science 20 December 2002:
Vol. 298. no. 5602, pp. 2401 - 2403
DOI: 10.1126/science.1078376
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Reports
Coordinated Nonvectorial Folding in a Newly Synthesized Multidomain Protein
Annemieke Jansens,*
Esther van Duijn,
Ineke Braakman
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.
Department of Bio-Organic Chemistry 1, Bijvoet Center for
Biomolecular Research, University of Utrecht, Padualaan 8, 3584 CH
Utrecht, Netherlands.
*
Present address: Biological Sciences, Stanford University, 325 Serra Mall, Stanford, CA 94305, USA.
To whom correspondence should be addressed. E-mail:
i.braakman{at}chem.uu.nl
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