Functional relationship between calreticulin, calnexin, and the endoplasmic reticulum luminal domain of calnexin.
Calnexin is a membrane protein of the endoplasmic reticulum (ER) that functions as a molecular chaperone and as a component of the ER quality control machinery. Calreticulin, a soluble analog of calnexin, is thought to possess similar functions, but these have not been directly demonstrated in vivo. Both proteins contain a lectin site that directs their association with newly synthesized glycoproteins. Although many glycoproteins bind to both calnexin and calreticulin, there are differences in the spectrum of glycoproteins that each binds. Using a Drosophila expression system and the mouse class I histocompatibility molecule as a model glycoprotein, we found that calreticulin does possess apparent chaperone and quality control functions, enhancing class I folding and subunit assembly, stabilizing subunits, and impeding export of assembly intermediates from the ER. Indeed, the functions of calnexin and calreticulin were largely interchangeable. We also determined that a soluble form of calnexin (residues 1-387) can functionally replace its membrane-bound counterpart. However, when calnexin was expressed as a soluble protein in L cells, the pattern of associated glycoproteins changed to resemble that of calreticulin. Conversely, membrane-anchored calreticulin bound to a similar set of glycoproteins as calnexin. Therefore, the different topological environments of calnexin and calreticulin are important in determining their distinct substrate specificities.
Danilczyk
U G
UG
Department of Immunology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
Cohen-Doyle
M F
MF
Williams
D B
DB
D000818:Animals; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D037281:Calnexin; D037282:Calreticulin; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry; D003593:Cytoplasm / Q000737:chemistry; D004331:Drosophila melanogaster; D004721:Endoplasmic Reticulum / Q000737:chemistry*; D051379:Mice; D016296:Mutagenesis; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D012261:Ribonucleoproteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D013379:Substrate Specificity; D013997:Time Factors; D014162:Transfection; D001613:beta 2-Microglobulin / Q000378:metabolism
D002135:Calcium-Binding Proteins; D037282:Calreticulin; D012261:Ribonucleoproteins; D001613:beta 2-Microglobulin; D037281:Calnexin