Mutational suppression of transferrin receptor shedding can be compensated by distinct metalloproteases acting on alternative sites.
The human transferrin receptor (TfR) is proteolytically cleaved at R100 within the juxtamembrane stalk and to a lesser extent at an alternative site. We examined the effect of stalk mutations on human TfR shedding in transfected CHO cells. Point mutations at R100 led to an increase in alternative shedding while the R100 cleavage product was undetectable. Replacing the TfR-stalk by the corresponding sequences from tumor necrosis factor-alpha or interleukin-6 receptor also led to TfR ectodomain shedding. These results show that cleavage at alternative sites can compensate for suppressed cleavage at the major site and inhibitor studies reveal that at least three metalloproteases are involved in the shedding process.
Dassler
Katrin
K
Institut für Klinische Chemie und Pathobiochemie, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, 12200 Berlin, Germany.
Kaup
Matthias
M
Tauber
Rudolf
R
Fuchs
Hendrik
H
D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D006224:Cricetinae; D006801:Humans; D008666:Metalloendopeptidases / Q000378:metabolism*; D009154:Mutation; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D019947:Receptors, Interleukin-6 / Q000737:chemistry; D011990:Receptors, Transferrin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry
D019947:Receptors, Interleukin-6; D011990:Receptors, Transferrin; D014409:Tumor Necrosis Factor-alpha; D008666:Metalloendopeptidases