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Investigation of the biophysical and cell biological properties of ferroportin, a multipass integral membrane protein iron exporter

Rice, Adrian E. and Mendez, Michael J. and Hokanson, Craig A. and Rees, Douglas C. and Bjorkman, Pamela J. (2009) Investigation of the biophysical and cell biological properties of ferroportin, a multipass integral membrane protein iron exporter. Journal of Molecular Biology, 386 (3). pp. 717-732. ISSN 0022-2836. PMCID PMC2677177. https://resolver.caltech.edu/CaltechAUTHORS:20090422-143224842

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Abstract

Ferroportin is a multipass membrane protein that serves as an iron exporter in many vertebrate cell types. Ferroportin-mediated iron export is controlled by the hormone hepcidin, which binds ferroportin, causing its internalization and degradation. Mutations in ferroportin cause a form of the iron overload hereditary disease hemochromatosis. Relatively little is known about ferroportin's properties or the mechanism by which mutations cause disease. In this study, we expressed and purified human ferroportin to characterize its biochemical/biophysical properties in solution and conducted cell biological studies in mammalian cells. We found that purified detergent-solubilized ferroportin is a well-folded monomer that binds hepcidin. In cell membranes, the N- and C-termini were both cytosolic, implying an even number of transmembrane regions, and ferroportin was mainly localized to the plasma membrane. Hepcidin addition resulted in a redistribution of ferroportin to intracellular compartments that labeled with early endosomal and lysosomal, but not Golgi, markers and that trafficked along microtubules. An analysis of 16 disease-related ferroportin mutants revealed that all were expressed and trafficked to the plasma membrane but that some were resistant to hepcidin-induced internalization. The characterizations reported here form a basis upon which models for ferroportin's role in regulating iron homeostasis in health and disease can be interpreted.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1016/j.jmb.2008.12.063DOIArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2677177/PubMed CentralArticle
ORCID:
AuthorORCID
Rees, Douglas C.0000-0003-4073-1185
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© 2008 Elsevier Ltd. Received 16 October 2008; revised 3 December 2008; accepted 22 December 2008. Edited by J. Bowie. Available online 3 January 2009. This work was supported by the National Institutes of Health through grant 1R01 DK60770- 01 (to P.J.B.) and a National Science Foundation Graduate Research Fellowship (A.E.R.). We thank members of the Bjorkman laboratory for critical reading of the manuscript and the Caltech Protein Expression Center for virus construction and high titer virus production.
Funders:
Funding AgencyGrant Number
NIH1R01 DK6077001
NSF Graduate Research FellowshipUNSPECIFIED
Subject Keywords:ferroportin; hemochromatosis; hepcidin; membrane protein; live-cell imaging
Issue or Number:3
PubMed Central ID:PMC2677177
Record Number:CaltechAUTHORS:20090422-143224842
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20090422-143224842
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:14048
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:10 Jul 2009 21:59
Last Modified:03 Oct 2019 00:46

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