Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.4.25.1 (
proteasome
)
28,817
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Hunter's syndrome (mucopolysaccharidosis type II) is a rare X-linked lysosomal storage disorder caused by mutations in the
iduronate-2-sulfatase
(
IDS
) gene. Motivated by the case of a child affected by this syndrome, we compared the intracellular fate of wild-type
IDS
(
IDS
WT
) and four nonsense mutations of
IDS
(
IDS
L482X
,
IDS
Y452X
,
IDS
R443X
, and
IDS
W337X
) generating progressively shorter forms of
IDS
associated with mild to severe forms of the disease. Our analyses revealed formylation of all forms of
IDS
at cysteine 84, which is a prerequisite for enzymatic activity. After formylation,
IDS
WT
was transported within lysosomes, where it was processed in the mature form of the enzyme. The length of disease-causing deletions correlated with gravity of the folding and transport phenotype, which was anticipated by molecular dynamics analyses. The shortest form of
IDS
,
IDS
W337X
, was retained in the endoplasmic reticulum (ER) and degraded by the ubiquitin-
proteasome
system.
IDS
R443X
,
IDS
Y452X
, and
IDS
L482X
passed ER quality control and were transported to the lysosomes, but failed lysosomal quality control, resulting in their rapid clearance and in loss-of-function phenotype. Failure of ER quality control inspection is an established cause of loss of function observed in protein misfolding diseases. Our data reveal that fulfillment of ER requirements might not be sufficient, highlight lysosomal quality control as the distal station to control lysosomal enzymes fitness and pave the way for alternative therapeutic interventions.
...
PMID:Endoplasmic Reticulum and Lysosomal Quality Control of Four Nonsense Mutants of Iduronate 2-Sulfatase Linked to Hunter's Syndrome. 3189 84
