Highlights d Simulation of membrane association for 81 of the 114 E. coli lipoproteins d The lipoprotein chaperone, LolB, has a major binding orientation with a membrane d LolCDE deforms the membrane to initiate lipoprotein transfer d Transport across the periplasm, from LolA to LolB, is thermodynamically favorable

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The two clathrin isoforms, CHC17 and CHC22, generate separate vesicles for intracellular transport. CHC17 mediates endocytosis and housekeeping membrane traffic in all cells. CHC22, expressed most highly in skeletal muscle, transports the glucose transporter GLUT4 from the endoplasmic-reticulum-to-Golgi intermediate compartment (ERGIC) to an intracellular GLUT4 storage compartment (GSC) from where GLUT4 is mobilized by insulin. Molecular determinants distinguishing the trafficking of CHC22 clathrin from CHC17 within the GLUT4 pathway are defined in this study. The C-terminal trimerization domain of CHC22, but not CHC17, directly binds SNX5, which also binds the ERGIC tether p115. SNX5, and the functionally redundant SNX6, are required for CHC22 localization independently of their participation in the endosomal ESCPE-1 complex. Both the SNX5-BAR domain and an isoform-specific patch on the CHC22 N-terminal domain separately mediate binding to p115, and both interactions are required for CHC22 recruitment. These indirect and direct interactions at each CHC22 terminus are required for GLUT4 traffic to the GSC, defining a dual mechanism regulating the function of CHC22 in glucose metabolism.Summary statementCHC22 clathrin uses a bipartite mechanism for recruitment to the early secretory pathway, where it targets the GLUT4 transporter to an insulin-responsive intracellular compartment. Localization requires binding to the ERGIC tether p115 through sorting nexin 5 interaction at the CHC22 C-terminus and directly via the CHC22 N-terminal domain.

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