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Crystal structure of a hemojuvelin-binding fragment of neogenin at 1.8 Å

Yang, Fan and West, Anthony P., Jr. and Bjorkman, Pamela J. (2011) Crystal structure of a hemojuvelin-binding fragment of neogenin at 1.8 Å. Journal of Structural Biology, 174 (1). pp. 239-244. ISSN 1047-8477. PMCID PMC3074981.

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Neogenin is a type I transmembrane glycoprotein with a large ectodomain containing tandem immunoglobulin-like and fibronectin type III (FNIII) domains. Closely related to the tumor suppressor gene DCC, neogenin functions in critical biological processes through binding to various ligands, including netrin, repulsive guidance molecules, and the iron regulatory protein hemojuvelin. We previously reported that neogenin binds to hemojuvelin through its membrane-proximal fifth and sixth FNIII domains (FN5–6), with domain 6 (FN6) contributing the majority of critical binding interactions. Here we present the crystal structure of FN5–6, the hemojuvelin-binding fragment of human neogenin, at 1.8 Å. The two FNIII domains are orientated nearly linearly, a domain arrangement most similar to that of a tandem FNIII-containing fragment within the cytoplasmic tail of the β4 integrin. By mapping surface-exposed residues that differ between neogenin FN5–6 and the comparable domains from DCC, which does not bind hemojuvelin, we identified a potential hemojuvelin-binding site on neogenin FN6. Neogenin FN5, which does not bind hemojuvelin in isolation, exhibits a highly electropositive surface, which may be involved in interactions with negatively-charged polysaccharides or phospholipids in the membrane bilayer. The neogenin FN5–6 structure can be used to facilitate a molecular understanding of neogenin’s interaction with hemojuvelin to regulate iron homeostasis and with hemojuvelin-related repulsive guidance molecules to mediate axon guidance.

Item Type:Article
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URLURL TypeDescription CentralArticle
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© 2010 Elsevier Inc. Received 4 August 2010; revised 12 October 2010; accepted 13 October 2010; Available online 22 October 2010. We thank Inder Nangiana and the Caltech Protein Expression Center for assistance with protein expression, Pavle Nickolovski and the Caltech Molecular Observatory for assistance with automated crystallization, Dr. Leonard Thomas for help with X-ray data collection, and members of the Bjorkman lab for critical reading of the manuscript. The authors acknowledge the Gordon and Betty Moore Foundation for support of the Molecular Observatory at Caltech.
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Gordon and Betty Moore FoundationUNSPECIFIED
Subject Keywords:Neogenin; Hemojuvelin; Crystal structure; FNIII domain; Iron homeostasis; Repulsive guidance molecule
Issue or Number:1
PubMed Central ID:PMC3074981
Record Number:CaltechAUTHORS:20110421-161208459
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Official Citation:Fan Yang, Anthony P. West Jr., Pamela J. Bjorkman, Crystal structure of a hemojuvelin-binding fragment of neogenin at 1.8 A, Journal of Structural Biology, Volume 174, Issue 1, April 2011, Pages 239-244, ISSN 1047-8477, DOI: 10.1016/j.jsb.2010.10.005.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:23421
Deposited By: Jason Perez
Deposited On:22 Apr 2011 17:24
Last Modified:03 Oct 2019 02:46

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