CaltechAUTHORS
  A Caltech Library Service

Neogenin Interacts with Hemojuvelin through Its Two Membrane-Proximal Fibronectin Type III Domains

Yang, Fan and West, Anthony P. and Allendorph, George P. and Choe, Senyon and Bjorkman, Pamela J. (2008) Neogenin Interacts with Hemojuvelin through Its Two Membrane-Proximal Fibronectin Type III Domains. Biochemistry, 47 (14). pp. 4237-4245. ISSN 0006-2960. PMCID PMC2819367. doi:10.1021/bi800036h. https://resolver.caltech.edu/CaltechAUTHORS:20170201-074623072

[img] PDF (ACS AuthorChoice) - Published Version
See Usage Policy.

3MB
[img] PDF - Accepted Version
See Usage Policy.

2MB
[img] PDF (File 3. Neogenin Interacts with Hemojuvelin through Its Two Membrane-Proximal Fibronectin Type III Domains) - Supplemental Material
See Usage Policy.

199kB
[img] PDF (File 4. Neogenin Interacts with Hemojuvelin through Its Two Membrane-Proximal Fibronectin Type III Domains) - Supplemental Material
See Usage Policy.

54kB

Use this Persistent URL to link to this item: https://resolver.caltech.edu/CaltechAUTHORS:20170201-074623072

Abstract

Hemojuvelin is a recently identified iron-regulatory protein that plays an important role in affecting the expression of hepcidin, a key iron regulatory hormone. Although the underlying mechanism of this process is not clear, several hemojuvelin-binding proteins, including the cell surface receptor neogenin and bone morphogenetic protein (BMP) cytokines, have been identified. The ectodomain of neogenin is composed of four immunoglobulin-like (Ig) domains followed by six fibronectin type III-like (FNIII) domains. Here we report expression of soluble versions of hemojuvelin and neogenin for biochemical characterization of their interaction and the interaction of HJV with BMP-2. Hemojuvelin normally undergoes an autocatalytic cleavage, and as in vivo, recombinant hemojuvelin exists as a mixture of cleaved and uncleaved forms. Neogenin binds to cleaved and noncleaved hemojuvelin, as verified by its binding to an uncleaved mutant hemojuvelin. We localized the hemojuvelin binding site on neogenin to the membrane-proximal fifth and sixth FNIII domains and the juxtamembrane linker and showed that a fragment containing only this region binds 2–3 orders of magnitude more tightly than the entire neogenin ectodomain. Binding to the most membrane-proximal region of neogenin may play a role in regulating the levels of soluble and membrane-bound forms of hemojuvelin, which in turn would influence the amount of free BMP-2 available for binding to its receptors and triggering transcription of the hepcidin gene. Our finding that BMP-2 and neogenin bind simultaneously to hemojuvelin raises the possibility that neogenin is part of a multiprotein complex at the hepatocyte membrane involving BMP, its receptors, and hemojuvelin.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/bi800036hDOIArticle
http://pubs.acs.org/doi/full/10.1021/bi800036hPublisherArticle
http://pubs.acs.org/doi/suppl/10.1021/bi800036hPublisherSupporting Information
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2819367/PubMed CentralArticle
ORCID:
AuthorORCID
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© 2008 American Chemical Society. ACS AuthorChoice. Received 8 January 2008. Date accepted 20 February 2008. Published online 13 March 2008. Published in print 1 April 2008. This work was supported by the National Institutes of Health (1R01 DK60770 to P.J.B.). We thank Caroline Enns and An-Sheng Zhang (Oregon Health and Sciences University) for cDNAs, sharing unpublished data, and critical reading of the manuscript, Inderjit Nangiana at the Caltech Protein Expression Center for assistance with protein expression, G. Hathaway and the Caltech PPMAL for N-terminal sequencing, Richard Olson for help with analytical ultracentrifugation, and Adrian Rice for assistance with light scattering experiments.
Funders:
Funding AgencyGrant Number
NIH1R01 DK60770
Issue or Number:14
PubMed Central ID:PMC2819367
DOI:10.1021/bi800036h
Record Number:CaltechAUTHORS:20170201-074623072
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170201-074623072
Official Citation:Neogenin Interacts with Hemojuvelin through Its Two Membrane-Proximal Fibronectin Type III Domains Fan Yang, Anthony P. West, Jr., George P. Allendorph, Senyon Choe, and Pamela J. Bjorkman Biochemistry 2008 47 (14), 4237-4245 DOI: 10.1021/bi800036h
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:73907
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:01 Feb 2017 20:32
Last Modified:11 Nov 2021 05:23

Repository Staff Only: item control page