TY - JOUR
T1 - Mammalian O-mannosylation of Cadherins and Plexins is Independent of Protein O-mannosyltransferase 1 and 2
AU - Larsen, Ida Signe Bohse
AU - Narimatsu, Yoshiki
AU - Joshi, Hiren Jitendra
AU - Yang, Zhang
AU - Harrison, Oliver J
AU - Brasch, Julia
AU - Shapiro, Lawrence
AU - Honig, Barry
AU - Vakhrushev, Sergey Y
AU - Clausen, Henrik
AU - Halim, Adnan
N1 - Copyright © 2017, The American Society for Biochemistry and Molecular Biology.
PY - 2017/7/7
Y1 - 2017/7/7
N2 - Protein O-mannosylation is found in yeast and metazoans, and a family of conserved orthologous protein O-mannosyl-transferases is believed to initiate this important post-translational modification. We recently discovered that the cadherin superfamily carries O-linked mannose (O-Man) glycans at highly conserved residues in specific extracellular cadherin domains, and it was suggested that the function of E-cadherin was dependent on the O-Man glycans. Deficiencies in enzymes catalyzing O-Man biosynthesis, including the two human protein O-mannosyltransferases, POMT1 and POMT2, underlie a subgroup of congenital muscular dystrophies designated α-dystroglycanopathies, because deficient O-Man glycosylation of α-dystroglycan disrupts laminin interaction with α-dystroglycan and the extracellular matrix. To explore the functions of O-Man glycans on cadherins and protocadherins, we used a combinatorial gene-editing strategy in multiple cell lines to evaluate the role of the two POMTs initiating O-Man glycosylation and the major enzyme elongating O-Man glycans, the protein O-mannose β-1,2-N-acetylglucosaminyltransferase, POMGnT1. Surprisingly, O-mannosylation of cadherins and protocadherins does not require POMT1 and/or POMT2 in contrast to α-dystroglycan, and moreover, the O-Man glycans on cadherins are not elongated. Thus, the classical and evolutionarily conserved POMT O-mannosylation pathway is essentially dedicated to α-dystroglycan and a few other proteins, whereas a novel O-mannosylation process in mammalian cells is predicted to serve the large cadherin superfamily and other proteins.
AB - Protein O-mannosylation is found in yeast and metazoans, and a family of conserved orthologous protein O-mannosyl-transferases is believed to initiate this important post-translational modification. We recently discovered that the cadherin superfamily carries O-linked mannose (O-Man) glycans at highly conserved residues in specific extracellular cadherin domains, and it was suggested that the function of E-cadherin was dependent on the O-Man glycans. Deficiencies in enzymes catalyzing O-Man biosynthesis, including the two human protein O-mannosyltransferases, POMT1 and POMT2, underlie a subgroup of congenital muscular dystrophies designated α-dystroglycanopathies, because deficient O-Man glycosylation of α-dystroglycan disrupts laminin interaction with α-dystroglycan and the extracellular matrix. To explore the functions of O-Man glycans on cadherins and protocadherins, we used a combinatorial gene-editing strategy in multiple cell lines to evaluate the role of the two POMTs initiating O-Man glycosylation and the major enzyme elongating O-Man glycans, the protein O-mannose β-1,2-N-acetylglucosaminyltransferase, POMGnT1. Surprisingly, O-mannosylation of cadherins and protocadherins does not require POMT1 and/or POMT2 in contrast to α-dystroglycan, and moreover, the O-Man glycans on cadherins are not elongated. Thus, the classical and evolutionarily conserved POMT O-mannosylation pathway is essentially dedicated to α-dystroglycan and a few other proteins, whereas a novel O-mannosylation process in mammalian cells is predicted to serve the large cadherin superfamily and other proteins.
U2 - 10.1074/jbc.m117.794487
DO - 10.1074/jbc.m117.794487
M3 - Journal article
C2 - 28512129
SN - 0021-9258
VL - 292
SP - 11586
EP - 11598
JO - The Journal of Biological Chemistry
JF - The Journal of Biological Chemistry
ER -