Identification of the pH-dependent membrane anchor of carboxypeptidase E (EC 3.4.17.10).

Carboxypeptidase E Is a Regulated Secretory Pathway Sorting Receptor: Genetic Obliteration Leads to Endocrine Disorders in Cpefat Mice

“…It has the capacity to specifically bind tor. It has an amphipathic tail at the C-terminus (Fricker et al, 1990;. It has been N-POMC1-26 containing the 13 amino acid amphipathic loop (N-POMC8-20) RSP sorting signal of POMC, full-proposed that the hydrophobic residues in the amphipathic tail are buried in the lipid bilayer or interact with length POMC, proinsulin, proenkephalin, and chromogranin A, in an N-POMC1-26 displaceable manner.…”

Protein secretion: Puzzling receptors

“…The second observation is that many regulated secretory proteins associate tightly with the luminal leaflet of the membrane. In neuroendocrine cells, membrane-associated forms have been described for all types of regulated secretory protein: peptides, such as insulin or adrenocorticotropic hormone (ACTH) [12], processing enzymes, such as CPE [13] and prohormone convertases [14], and other secretory granule constituents of unknown function, such as the granins [12]. Membrane association of these proteins can been detected at the level of the trans-Golgi network and persists through secretory granule biogenesis and exocytosis, so that cell-surface-associated immunoreactivity for these proteins can be detected when regulated secretion is induced [12].…”

“…The various regulated secretory proteins differ in the proportion in which they exist in membrane-associated form, and the nature of their membrane anchorage is understood in only a few cases (for example, [13]). Nonetheless, given the ability and tendency of regulated secretory proteins to engage in homophilic and heterophilic interactions, the membrane-associated forms of these proteins can be regarded as 'sorting receptors', in that their existence provides a simple mechanism for the membrane enveloping of aggregated regulated secretory proteins, and hence for the budding of an immature secretory granule containing a selected set of secretory proteins [3,12] (Figure 1).…”

Inside the Insulin Secretory Granule

“…Carboxypeptidase E. CPE, also known as CPH, exists in both soluble and membrane-associated forms in β-cells [ 170 ]. An alpha-helix in the C-terminus of CPE anchors through cholesterol rich lipid rafts of the secretory pathway membrane, leaving six residues protruding to the cytoplasm [ 171 , 172 ] ( Figure 5 ). Importantly, penetration through the membrane only occurs at or below pH 6 [ 172 ], conditions reflecting the late Golgi and SG compartments but not the proximal Golgi or ER [ 173 ] ( Figure 1 ).…”

“…An alpha-helix in the C-terminus of CPE anchors through cholesterol rich lipid rafts of the secretory pathway membrane, leaving six residues protruding to the cytoplasm [ 171 , 172 ] ( Figure 5 ). Importantly, penetration through the membrane only occurs at or below pH 6 [ 172 ], conditions reflecting the late Golgi and SG compartments but not the proximal Golgi or ER [ 173 ] ( Figure 1 ). Several lines of evidence have also demonstrated that membrane-bound forms of CPE can aggregate at this pH with at least 1 mM Ca 2+ [ 174 ], and co-immunoprecipitate in these conditions with both pro-opiomelanocortin and insulin in vitro [ 175 ].…”