Mutant Sec61p is a substrate of ER degradation

1
Mutant Sec61p is a substrate of ER degradation
The evidence indicates that translocon is
involved in ERAD.
2
Degradation of the Cystic Fibrosis Transmembrane
Conductance Regulator

• CFTR is a chloride channel expressed at the
  apical surface of polarized epithelial cells
• The majority of Caucasian cystic fibrosis
  patients have at least one copy of the ?F508
  mutation, a temperature sensitive allele that is
  unable to fold correctly at physiological
  temperatures
• The mutant protein would function normally at
  the plasma membrane however, its improperly
  folded state targets it for degradation
• Evidence has shown that CFTR is rapidly degraded
  in the ubiquitin-proteasome pathway

3

• The proteolytic activities of the proteasome are
  responsible for the vast majority of
  intracellular degradation of misfolded CFTR
  molecules

Gelman, MS, et al. J. Biol Chem 277 11709-14
4

• CFTR is polyubiquitinated prior to degradation

Xiong, X, et al. J. Biol. Chem 274 2616-24
5

• Degradation of CFTR requires several molecular
  chaperones, including the ubiquitin-conjugating
  enzymes (ubc6, ubc7) and the ubiquitin-protein
  ligase (Der3p), as well as the retrotranslocation
  pore component (Sec61p)

Kiser, GL, Archives of Biochemistry and
Biophysics 390 195-205, 2001
6

• Summary
• After import and glycosylation in the ER,
  misfolded proteins are exported out into the
  cytosol through the Sec61 complex and with the
  aid of chaperones.
• Once in the cytosol, they are ubiquitinated and
  degraded by the 26S proteasome.