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Evidence for the multimeric structure of ferroportin
Ivana De Domenico1, Diane McVey Ward, Giovanni Musci
1Department of Pathology, School of Medicine, University of Utah, Salt Lake City, UT 84132, USA.
Blood
|November 2, 2006
Summary
Mutations in ferroportin (Fpn), an iron transporter, cause dominant iron overload. This study confirms Fpn forms dimers, supporting the dominant-negative mechanism of disease inheritance.
Area of Science:
- Biochemistry
- Cell Biology
- Genetics
Background:
- Ferroportin (Fpn) is the sole known cellular iron exporter.
- Mutations in Fpn cause a dominant form of iron overload disease.
- Previous studies have yielded conflicting data regarding Fpn multimerization.
Purpose of the Study:
- To investigate the oligomeric state of ferroportin (Fpn).
- To determine if Fpn forms multimers and if this is affected by epitope tagging or overexpression.
- To provide evidence supporting the dominant-negative mechanism in Fpn-related iron overload.
Main Methods:
- Epitope tagging of wild-type Fpn with GFP, FLAG, and c-myc.
- Co-expression of different epitope-tagged Fpn constructs in cultured cells.
- Co-immunoprecipitation and chemical crosslinking followed by Western blot analysis.
Main Results:
- Quantitative co-immunoprecipitation of co-expressed epitope-tagged Fpn proteins.
- Chemical crosslinking confirmed the association of Fpn-GFP and Fpn-FLAG.
- Endogenous Fpn was shown to exist as a dimer in rat and mouse cells.
Conclusions:
- Ferroportin (Fpn) exists as a dimer in cells.
- These findings support the hypothesis that mutant Fpn proteins exert dominant-negative effects.
- This mechanism explains the dominant inheritance pattern observed in Fpn-iron overload disease.
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