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Structural features within the nascent chain regulate alternative targeting of secretory proteins to mitochondria

Natalie V Pfeiffer, Daniela Dirndorfer, Sven Lang, Ulrike K Resenberger, Lisa M Restelli, Charles Hemion, Margit Miesbauer, Stephan Frank, Albert Neutzner, Richard Zimmermann, Konstanze F Winklhofer, Jörg Tatzelt

Author Affiliations

  1. Natalie V Pfeiffer1,
  2. Daniela Dirndorfer1,
  3. Sven Lang2,,
  4. Ulrike K Resenberger1,,
  5. Lisa M Restelli3,
  6. Charles Hemion4,
  7. Margit Miesbauer1,,
  8. Stephan Frank3,
  9. Albert Neutzner4,
  10. Richard Zimmermann2,
  11. Konstanze F Winklhofer1,5 and
  12. Jörg Tatzelt*,1,5
  1. 1 Neurobiochemistry, Adolf‐Butenandt‐Institute, Ludwig‐Maximilians‐University Munich, Munich, Germany
  2. 2 Medical Biochemistry and Molecular Biology, Saarland University Homburg, Homburg, Germany
  3. 3 Department of Neuropathology, Institute of Pathology, University of Basel, Basel, Switzerland
  4. 4 Department of Biochemistry, and Department for Ophthalmology, University of Basel, Basel, Switzerland
  5. 5 German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
  1. *Corresponding author. Department of Biochemistry, Neurobiochemistry, Ludwig‐Maximilians‐University Munich, Schillerstrasse 44, Munich, 80336, Germany. Tel.:+49 89 2180 75442; Fax:+49 89 2180 75415; E-mail: joerg.tatzelt{at}med.uni-muenchen.de
  1. These authors contributed equally to this work

  • Present address: Roche Pharma AG, 79639 Grenzach‐Wyhlen, Germany

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Abstract

Protein targeting to specified cellular compartments is essential to maintain cell function and homeostasis. In eukaryotic cells, two major pathways rely on N‐terminal signal peptides to target proteins to either the endoplasmic reticulum (ER) or mitochondria. In this study, we show that the ER signal peptides of the prion protein‐like protein shadoo, the neuropeptide hormone somatostatin and the amyloid precursor protein have the property to mediate alternative targeting to mitochondria. Remarkably, the targeting direction of these signal peptides is determined by structural elements within the nascent chain. Each of the identified signal peptides promotes efficient ER import of nascent chains containing α‐helical domains, but targets unstructured polypeptides to mitochondria. Moreover, we observed that mitochondrial targeting by the ER signal peptides correlates inversely with ER import efficiency. When ER import is compromised, targeting to mitochondria is enhanced, whereas improving ER import efficiency decreases mitochondrial targeting. In conclusion, our study reveals a novel mechanism of dual targeting to either the ER or mitochondria that is mediated by structural features within the nascent chain.

  • Received August 31, 2012.
  • Accepted February 1, 2013.
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