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: UNIPROT:P11021 (
BiP
)
2,049
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Missense mutation is the most common mutation type in hemophilia. However, the majority of missense mutations remain uncharacterized. Here we characterize how hemophilia mutations near the unused N-glycosylation site of the A2 domain (N582) of
FVIII
affect protein conformation and intracellular trafficking. N582 is located in the middle of a short 3
10
-helical turn (D580-S584), in which most amino acids have multiple hemophilia mutations. All 14 missense mutations found in this 3
10
-helix reduced secretion levels of the A2 domain and full-length
FVIII
. Secreted mutants have decreased activities relative to WT
FVIII
. Selected mutations also lead to partial glycosylation of N582, suggesting that rapid folding of local conformation prevents glycosylation of this site in wild-type
FVIII
. Protease sensitivity, stability and degradation of the A2 domain vary among mutants, and between non-glycosylated and glycosylated species of the same mutant. Most of the mutants interact with the ER chaperone
BiP
, while only mutants with aberrant glycosylation interact with calreticulin. Our results show that the short 3
10
-helix from D580 to S584 is critical for proper biogenesis of the A2 domain and
FVIII
, and reveal a range of molecular mechanisms by which
FVIII
missense mutations lead to moderate to severe hemophilia A.
...
PMID:Missense mutations near the N-glycosylation site of the A2 domain lead to various intracellular trafficking defects in coagulation factor VIII. 2832 46
