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: UMLS:C0268318 (
ICP
)
10,007
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Somatic mutations that perturb Parkin ubiquitin ligase activity and the misregulation of iron homeostasis have both been linked to Parkinson's disease.
Lactotransferrin
(
LTF
) is a member of the family of transferrin iron binding proteins that regulate iron homeostasis, and increased levels of
LTF
and its receptor have been observed in neurodegenerative disorders like Parkinson's disease. Here, we report that Parkin binds to
LTF
and ubiquitylates
LTF
to influence iron homeostasis. Parkin-dependent ubiquitylation of
LTF
occurred most often on lysines (K) 182 and 649. Substitution of K182 or K649 with alanine (K182A or K649A, respectively) led to a decrease in the level of
LTF
ubiquitylation, and substitution at both sites led to a major decrease in the level of
LTF
ubiquitylation. Importantly, Parkin-mediated ubiquitylation of
LTF
was critical for regulating intracellular iron levels as overexpression of
LTF
ubiquitylation site point mutants (K649A or K182A/K649A) led to an increase in intracellular iron levels measured by
ICP
-MS/MS. Consistently, RNAi-mediated depletion of Parkin led to an increase in intracellular iron levels in contrast to overexpression of Parkin that led to a decrease in intracellular iron levels. Together, these results indicate that Parkin binds to and ubiquitylates
LTF
to regulate intracellular iron levels. These results expand our understanding of the cellular processes that are perturbed when Parkin activity is disrupted and more broadly the mechanisms that contribute to Parkinson's disease.
...
PMID:Regulation of Iron Homeostasis through Parkin-Mediated Lactoferrin Ubiquitylation. 3278 4
