Paralog of the formylglycine-generating enzyme--retention in the endoplasmic reticulum by canonical and noncanonical signals.
Formylglycine-generating enzyme (FGE) catalyzes in newly synthesized sulfatases the oxidation of a specific cysteine residue to formylglycine, which is the catalytic residue required for sulfate ester hydrolysis. This post-translational modification occurs in the endoplasmic reticulum (ER), and is an essential step in the biogenesis of this enzyme family. A paralog of FGE (pFGE) also localizes to the ER. It shares many properties with FGE, but lacks formylglycine-generating activity. There is evidence that FGE and pFGE act in concert, possibly by forming complexes with sulfatases and one another. Here we show that human pFGE, but not FGE, is retained in the ER through its C-terminal tetrapeptide PGEL, a noncanonical variant of the classic KDEL ER-retention signal. Surprisingly, PGEL, although having two nonconsensus residues (PG), confers efficient ER retention when fused to a secretory protein. Inducible coexpression of pFGE at different levels in FGE-expressing cells did not significantly influence the kinetics of FGE secretion, suggesting that pFGE is not a retention factor for FGE in vivo. PGEL is accessible at the surface of the pFGE structure. It is found in 21 mammalian species with available pFGE sequences. Other species carry either canonical signals (eight mammals and 26 nonmammals) or different noncanonical variants (six mammals and six nonmammals). Among the latter, SGEL was tested and found to also confer ER retention. Although evolutionarily conserved for mammalian pFGE, the PGEL signal is found only in one further human protein entering the ER. Its consequences for KDEL receptor-mediated ER retrieval and benefit for pFGE functionality remain to be fully resolved.
Gande
Santosh Lakshmi
SL
Zentrum für Biochemie und Molekulare Zellbiologie, Abteilung Biochemie II, Universität Göttingen, Germany.
Mariappan
Malaiyalam
M
Schmidt
Bernhard
B
Pringle
Thomas H
TH
von Figura
Kurt
K
Dierks
Thomas
T
D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D019295:Computational Biology; D017124:Conserved Sequence; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D019143:Evolution, Molecular; D005998:Glycine / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D050862:Oxidoreductases Acting on Sulfur Group Donors; D011487:Protein Conformation; D021382:Protein Sorting Signals; D013429:Sulfatases / Q000032:analysis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D021382:Protein Sorting Signals; C032736:N-formylglycine; D050862:Oxidoreductases Acting on Sulfur Group Donors; C480483:SUMF1 protein, human; C500803:SUMF2 protein, human; D013429:Sulfatases; D005998:Glycine