Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 20 December 2002:
Vol. 298. no. 5602, pp. 2401 - 2403
DOI: 10.1126/science.1078376
Prev | Table of Contents | Next

Reports

Coordinated Nonvectorial Folding in a Newly Synthesized Multidomain Protein

Annemieke Jansens,* Esther van Duijn, Ineke Braakmandagger

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.

dagger    To whom correspondence should be addressed. E-mail: i.braakman{at}chem.uu.nl

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
ERp57 is involved in the oxidative folding of the low-density lipoprotein receptor in the endoplasmic reticulum.
J.-L. Berry and N. J. Bulleid (2009)
Bioscience Horizons 2, 13-21
   Abstract »    Full Text »    PDF »
Substrate Specificity of the Oxidoreductase ERp57 Is Determined Primarily by Its Interaction with Calnexin and Calreticulin.
C. E. Jessop, T. J. Tavender, R. H. Watkins, J. E. Chambers, and N. J. Bulleid (2009)
J. Biol. Chem. 284, 2194-2202
   Abstract »    Full Text »    PDF »
Chaperone displacement from mutant cystic fibrosis transmembrane conductance regulator restores its function in human airway epithelia.
F. Sun, Z. Mi, S. B. Condliffe, C. A. Bertrand, X. Gong, X. Lu, R. Zhang, J. D. Latoche, J. M. Pilewski, P. D. Robbins, et al. (2008)
FASEB J 22, 3255-3263
   Abstract »    Full Text »    PDF »
Bromophenol Blue Binding as a Probe to Study Urea and Guanidine Hydrochloride Denaturation of Bovine Serum Albumin.
A. A. Abd. Halim, H. A. Kadir, and S. Tayyab (2008)
J. Biochem. 144, 33-38
   Abstract »    Full Text »    PDF »
Scrambled Isomers as Key Intermediates in the Oxidative Folding of Ligand Binding Module 5 of the Low Density Lipoprotein Receptor.
X. Arias-Moreno, J. L. Arolas, F. X. Aviles, J. Sancho, and S. Ventura (2008)
J. Biol. Chem. 283, 13627-13637
   Abstract »    Full Text »    PDF »
In and Out of the ER: Protein Folding, Quality Control, Degradation, and Related Human Diseases.
D. N. Hebert and M. Molinari (2007)
Physiol Rev 87, 1377-1408
   Abstract »    Full Text »    PDF »
Cellular and molecular studies of Marfan syndrome mutations identify co-operative protein folding in the cbEGF12-13 region of fibrillin-1.
P. Whiteman, A. C. Willis, A. Warner, J. Brown, C. Redfield, and P. A. Handford (2007)
Hum. Mol. Genet. 16, 907-918
   Abstract »    Full Text »    PDF »
Disulfide formation as a probe of folding in GroEL-GroES reveals correct formation of long-range bonds and editing of incorrect short-range ones.
E. S. Park, W. A. Fenton, and A. L. Horwich (2007)
PNAS 104, 2145-2150
   Abstract »    Full Text »    PDF »
Binding characteristics of a panel of monoclonal antibodies against the ligand binding domain of the human LDLr.
A. T. Nguyen, T. Hirama, V. Chauhan, R. MacKenzie, and R. Milne (2006)
J. Lipid Res. 47, 1399-1405
   Abstract »    Full Text »    PDF »
Retention of Mutant Low Density Lipoprotein Receptor in Endoplasmic Reticulum (ER) Leads to ER Stress.
S. Sorensen, T. Ranheim, K. S. Bakken, T. P. Leren, and M. A. Kulseth (2006)
J. Biol. Chem. 281, 468-476
   Abstract »    Full Text »    PDF »
An Energy-dependent Maturation Step Is Required for Release of the Cystic Fibrosis Transmembrane Conductance Regulator from Early Endoplasmic Reticulum Biosynthetic Machinery.
J. Oberdorf, D. Pitonzo, and W. R. Skach (2005)
J. Biol. Chem. 280, 38193-38202
   Abstract »    Full Text »    PDF »
CADASIL mutations impair Notch3 glycosylation by Fringe.
J. F. Arboleda-Velasquez, R. Rampal, E. Fung, D. C. Darland, M. Liu, M. C. Martinez, C. P. Donahue, M. F. Navarro-Gonzalez, P. Libby, P. A. D'Amore, et al. (2005)
Hum. Mol. Genet. 14, 1631-1639
   Abstract »    Full Text »    PDF »
Intracellular fate of LDL receptor family members depends on the cooperation between their ligand-binding and EGF domains.
D. Van Hoof, K. W. Rodenburg, and D. J. Van der Horst (2005)
J. Cell Sci. 118, 1309-1320
   Abstract »    Full Text »    PDF »
Identification and Characterization of a Novel Thioredoxin-related Transmembrane Protein of the Endoplasmic Reticulum.
J. Haugstetter, T. Blicher, and L. Ellgaard (2005)
J. Biol. Chem. 280, 8371-8380
   Abstract »    Full Text »    PDF »
Glutathione Directly Reduces an Oxidoreductase in the Endoplasmic Reticulum of Mammalian Cells.
C. E. Jessop and N. J. Bulleid (2004)
J. Biol. Chem. 279, 55341-55347
   Abstract »    Full Text »    PDF »
CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum.
S. J. Marciniak, C. Y. Yun, S. Oyadomari, I. Novoa, Y. Zhang, R. Jungreis, K. Nagata, H. P. Harding, and D. Ron (2004)
Genes & Dev. 18, 3066-3077
   Abstract »    Full Text »    PDF »
Glutathione Limits Ero1-dependent Oxidation in the Endoplasmic Reticulum.
S. N. Molteni, A. Fassio, M. R. Ciriolo, G. Filomeni, E. Pasqualetto, C. Fagioli, and R. Sitia (2004)
J. Biol. Chem. 279, 32667-32673
   Abstract »    Full Text »    PDF »
Global Defects in the Expression and Function of the Low Density Lipoprotein Receptor (LDLR) Associated with Two Familial Hypercholesterolemia Mutations Resulting in Misfolding of the LDLR Epidermal Growth Factor-AB Pair.
E. J. Boswell, H. Jeon, S. C. Blacklow, and A. K. Downing (2004)
J. Biol. Chem. 279, 30611-30621
   Abstract »    Full Text »    PDF »
Stress, Protein (Mis)folding, and Signaling: The Redox Connection.
R. Sitia and S. N. Molteni (2004)
Sci. STKE 2004, pe27
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)