title: Structural features within the nascent chain regulate alternative targeting of secretory proteins to mitochondria.
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.
authors.affiliation: Neurobiochemistry, Adolf-Butenandt-Institute, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Natalie V
authors.initials: NV
authors.lastname: Pfeiffer
authors.forename: Daniela
authors.initials: D
authors.lastname: Dirndorfer
authors.forename: Sven
authors.initials: S
authors.lastname: Lang
authors.forename: Ulrike K
authors.initials: UK
authors.lastname: Resenberger
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Restelli
authors.forename: Charles
authors.initials: C
authors.lastname: Hemion
authors.forename: Margit
authors.initials: M
authors.lastname: Miesbauer
authors.forename: Stephan
authors.initials: S
authors.lastname: Frank
authors.forename: Albert
authors.initials: A
authors.lastname: Neutzner
authors.forename: Richard
authors.initials: R
authors.lastname: Zimmermann
authors.forename: Konstanze F
authors.initials: KF
authors.lastname: Winklhofer
authors.forename: Jörg
authors.initials: J
authors.lastname: Tatzelt
mesh_terms: D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D021382:Protein Sorting Signals; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000235:genetics; D013004:Somatostatin / Q000235:genetics / Q000378:metabolism*
chemical_list: D058851:GPI-Linked Proteins; D009419:Nerve Tissue Proteins; D021382:Protein Sorting Signals; C478971:SPRN protein, human; D013004:Somatostatin