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Fig. 3. pH-dependent sorting between the ER and ERGIC. Proteins travel between the ER and the ERGIC in anterograde and retrograde directions. The pH of the ER is 7.4 (Wu et al., 2001), whereas that of the ERGIC is more acidic. The scheme shows three different pH-dependent sorting mechanisms of anterograde-directed and/or recycling proteins in the early secretory pathway. ERGIC-53 functions as a transport receptor for the secretory/lysosomal protein procathepsin Z (pro-catZ). Association between ERGIC-53 and pro-catZ occurs in the ER at neutral pH, and dissociation occurs in the ERGIC following protonation of the ligand-binding site in ERGIC-53 (Appenzeller-Herzog et al., 2004). ERGIC-53 is then recycled back to the ER; pro-catZ proceeds through the secretory pathway. The LDL receptor-related protein (LRP) forms a complex with the escort protein RAP (Bu et al., 1995), which inhibits receptor-ligand interactions in the early secretory pathway. Again, low pH in the ERGIC triggers the dissociation of the two proteins. Subsequently, RAP is recycled back to the ER, probably by the KDEL receptor (KDEL-R), and LRP travels through the Golgi to the cell surface. By contrast, binding of the KDEL receptor to escaped ER proteins containing a C-terminal KDEL signal is thought to require the acidified pH in post-ER compartments (Scheel and Pelham, 1996). Ligand binding in turn triggers the retrograde transport of KDEL-receptor-ligand complexes from ERGIC and cis-Golgi to the ER.

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