A calmodulin-dependent translocation pathway for small secretory proteins

Cell. 2011 Dec 23;147(7):1576-88. doi: 10.1016/j.cell.2011.11.048.

Abstract

Metazoans secrete an extensive array of small proteins essential for intercellular communication, defense, and physiologic regulation. Their synthesis takes mere seconds, leaving minimal time for recognition by the machinery for cotranslational protein translocation into the ER. The pathway taken by these substrates to enter the ER is not known. Here, we show that both in vivo and in vitro, small secretory proteins can enter the ER posttranslationally via a transient cytosolic intermediate. This intermediate contained calmodulin selectively bound to the signal peptides of small secretory proteins. Calmodulin maintained the translocation competence of small-protein precursors, precluded their aggregation and degradation, and minimized their inappropriate interactions with other cytosolic polypeptide-binding proteins. Acute inhibition of calmodulin specifically impaired small-protein translocation in vitro and in cells. These findings establish a mammalian posttranslational pathway for small-protein secretion and identify an unexpected role for calmodulin in chaperoning these precursors safely through the cytosol.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimicrobial Cationic Peptides / chemistry
  • Antimicrobial Cationic Peptides / metabolism
  • Calmodulin / metabolism*
  • Endoplasmic Reticulum / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Metabolic Networks and Pathways
  • Prolactin / chemistry
  • Prolactin / metabolism
  • Protein Processing, Post-Translational
  • Protein Sorting Signals
  • Protein Transport
  • Proteins / chemistry
  • Proteins / metabolism*
  • Yeasts / metabolism

Substances

  • Antimicrobial Cationic Peptides
  • Calmodulin
  • Protein Sorting Signals
  • Proteins
  • cecropin A
  • Prolactin