title: The prodomain of a secreted hydrophobic mini-protein facilitates its export from the endoplasmic reticulum by hitchhiking on sorting receptors.
abstract: Misfolded secretory proteins are retained in the endoplasmic reticulum (ER) by quality control mechanisms targeted to exposed hydrophobic surfaces. Paradoxically, certain conotoxins expose extensive hydrophobic surfaces upon folding to their bioactive structures. How then can such secreted mini-proteins traverse the secretory pathway? Here we show that secretion of the hydrophobic conotoxin-TxVI is strongly dependent on its propeptide domain, which enhances TxVI export from the ER. The propeptide domain interacts with sorting receptors from the sortilin Vps10p domain family. The sortilin-TxVI interaction occurs in the ER, and sortilin facilitates export of TxVI from the ER to the Golgi. Thus, the prodomain in a secreted hydrophobic protein acts as a tag that can facilitate its ER export by a hitchhiking mechanism.
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, 76100 Rehovot, Israel.
authors.forename: Silvestro G
authors.initials: SG
authors.lastname: Conticello
authors.forename: Noga D
authors.initials: ND
authors.lastname: Kowalsman
authors.forename: Christian
authors.initials: C
authors.lastname: Jacobsen
authors.forename: Guennady
authors.initials: G
authors.lastname: Yudkovsky
authors.forename: Kazuki
authors.initials: K
authors.lastname: Sato
authors.forename: Zvulun
authors.initials: Z
authors.lastname: Elazar
authors.forename: Claus Munck
authors.initials: CM
authors.lastname: Petersen
authors.forename: Ami
authors.initials: A
authors.lastname: Aronheim
authors.forename: Mike
authors.initials: M
authors.lastname: Fainzilber
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport; D000595:Amino Acid Sequence; D000818:Animals; D001693:Biological Transport, Active; D019556:COS Cells; D020916:Conotoxins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008562:Membrane Glycoproteins / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D020916:Conotoxins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; D000099183:Sortilin