Title : Post-translational N-glycosylation of type I transmembrane
KCNE1 peptides : implications for membrane protein biogenesis and disease
Abstract :
- N-Glycosylation of membrane proteins is critical for their proper folding, co-assembly and subsequent matriculation through the secretory pathway
- Here, we examine the kinetics of N-glycan addition to type I transmembrane KCNE1 K(+) channel β-subunits , where point mutations that prevent N-glycosylation at one consensus site give rise to disorders of the cardiac rhythm and congenital deafness
- We show that KCNE1 has two distinct N-glycosylation sites : a typical co-translational site and a consensus site ∼20 residues away that unexpectedly acquires N-glycans after protein synthesis (post-translational)
- Mutations that ablate the co-translational site concomitantly reduce glycosylation at the post-translational site , resulting in unglycosylated KCNE1 subunits that cannot reach the cell surface with their cognate K(+) channel
- This long range inhibition is highly specific for post-translational N-glycosylation because mutagenic conversion of the KCNE1 post-translational site into a co-translational site restored both monoglycosylation and anterograde trafficking
- These results directly explain how a single point mutation can prevent N-glycan attachment at multiple sites , providing a new biogenic mechanism for human disease