A Calmodulin-Dependent Translocation Pathway for Small Secretory Proteins

SummaryMetazoans 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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (332 K)Download as PowerPoint slideHighlights► Unusually small secretory proteins enter the ER posttranslationally in vivo ► The signal sequences of small proteins are recognized by calmodulin in the cytosol ► Calmodulin shields hydrophobic signal sequences from aggregation and degradation ► The calmodulin pathway fills a niche that cannot be replaced by SRP or chaperones