Model of pro-αIIb interactions with the calnexin cycle. (A) The core N-linked glycan, Glc₃Man₉GlcNAc₂, is attached to the Asn at position 15 (N15) of pro-αIIb during translocation into the ER.(B) The glucosidases I and II (Gluc I + II) cleave off the glucose moieties, forming Glc₁Man₉GlcNAc₂, which is the glycan form recognized by calnexin (CNX). (C) Pro-αIIb remains bound to calnexin until the third glucose moiety is cleaved off by glucosidase II. (D) The glycan formed by removal of the third glucose, Man₉GlcNAc₂, is a substrate for UDP-glucose:glycoprotein glucosyltransferase (UGGT), which then reattaches a glucose moiety, recreating the Glc₁Man₉GlcNAc₂. Because incompletely folded glycoproteins (shown as squiggle) are substrates for UGGT, partially folded pro-αIIb subunits cycle between calnexin and UGGT, which provides additional time to achieve its native fold. There are 2 exits from the cycle: (E) Pro-αIIb may achieve its native fold (shown as spiral), at which point it is no longer a substrate for UGGT, and thus continues on the biogenesis pathway to complex formation with β3, or (F) the slowly active mannosidase I (Man I) may cleave the terminal mannose from the middle branch of the glycan, creating the structural signal that targets pro-αIIb to the proteasome for degradation via binding to the mannosidase-like protein EDEM and retrotranslocation out of the ER (not shown). Of note is the finding that proteasomal degradation of pro-αIIb continues at the normal rate in the presence of glucosidase inhibitors; thus pro-αIIb may proceed directly from step A to step F, without interaction with calnexin.