The N-terminal region of neuregulin isoforms determines the accumulation of cell surface and released neuregulin ectodomain.
Two neuregulin-1 isoforms highly expressed in the nervous system are the type III neuregulin III-beta1a and the type I neuregulin I-beta1a. The sequence of these two isoforms differs only in the region that is N-terminal of the bioactive epidermal growth factor-like domain. While the biosynthetic processing of the I-beta1a isoform has been well characterized, the processing of III-beta1a has not been reported. In this study, we compared III-beta1a and I-beta1a processing. Both III-beta1a and I-beta1a were synthesized as transmembrane proproteins that were proteolytically cleaved to produce an N-terminal fragment containing the bioactive epidermal growth factor-like domain. For I-beta1a, this product was released into the medium. However, for III-beta1a, this product was a transmembrane protein. In cultures of cells expressing III-beta1a, the amount of neuregulin at the cell surface was much greater, and the amount in the medium was much less than in cultures expressing I-beta1a. Phorbol ester treatment and truncation of the cytoplasmic tail had markedly different effects on III-beta1a and I-beta1a processing. These results demonstrate an important role for the N-terminal region in determining neuregulin biosynthetic processing and show that a major product of III-beta1a processing is a tethered ligand that may act as a cell surface signaling molecule.
Wang
J Y
JY
Department of Biology, Emory University, Atlanta, Georgia 30322, USA.
Miller
S J
SJ
Falls
D L
DL
D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000145:classification / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D017077:Culture Media, Conditioned; D008565:Membrane Proteins / Q000145:classification / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020890:Neuregulin-1 / Q000145:classification / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D020033:Protein Isoforms / Q000145:classification / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D011499:Protein Processing, Post-Translational
D002352:Carrier Proteins; D017077:Culture Media, Conditioned; D008565:Membrane Proteins; D020890:Neuregulin-1; D010446:Peptide Fragments; D020033:Protein Isoforms; D011498:Protein Precursors