Sec24 Is a Coincidence Detector that Simultaneously Binds Two Signals to Drive ER Export

Background: Incorporation of secretory proteins into ERderived vesicles involves recognition of cytosolic signals by
the COPII coat protein, Sec24. Additional cargo diversity is
achieved through cargo receptors, which include the Erv14/
Cornichon family that mediates export of transmembrane proteins despite the potential for such clients to directly interact
with Sec24. The molecular function of Erv14 thus remains unclear, with possible roles in COPII binding, membrane domain
chaperoning, and lipid organization.
Results: Using a targeted mutagenesis approach to define the
mechanism of Erv14 function, we identify conserved residues
in the second transmembrane domain of Erv14 that mediate
interaction with a subset of Erv14 clients. We further show
that interaction of Erv14 with a novel cargo-binding surface
on Sec24 is necessary for efficient trafficking of all of its clients.
However, we also determine that some Erv14 clients also
directly engage an adjacent cargo-binding domain of Sec24,
suggesting a novel mode of dual interaction between cargo
and coat.
Conclusions: We conclude that Erv14 functions as a canonical cargo receptor that couples membrane proteins to the
COPII coat, but that maximal export requires a bivalent signal
that derives from motifs on both the cargo protein and Erv14.
Sec24 can thus be considered a coincidence detector that
binds simultaneously to multiple signals to drive packaging
of polytopic membrane proteins. This mode of dual signal
binding to a single coat protein might serve as a general
mechanism to trigger efficient capture, or may be specifically
employed in ER export to control deployment of nascent
proteins.