INCREASED CELL-SURFACE EXPRESSION AND ENHANCED FOLDING IN THE ENDOPLASMIC-RETICULUM OF A MUTANT ERYTHROPOIETIN RECEPTOR

In both transfected and normal hematopoietic cells, the majority of ne wly made erythropoietin receptor (EPO-R) subunits are retained in the endoplasmic reticulum (ER), destined for degradation. Only a small fra ction exit the ER and are competent to bind EPO, suggesting that the E PO-R folds inefficiently. The EPO-R contains a 5-amino acid motif, WSX WS, in the extracellular domain that is conserved among members of the cytokine receptor family. We describe a mutant EPO-R with a change in the middle residue of this motif, A234E, that is transported from the ER more efficiently than the wild-type (wt) receptor and is expressed in elevated numbers at the cell surface. This mutant polypeptide is p rocessed more efficiently in the ER than its wt counterpart, suggestin g that it folds better than the wt EPO-R. Inefficient folding and proc essing of the wt EPO-R in the ER may be one mechanism for controlling the number of plasma membrane receptors.