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dc.contributor.authorOlsen, Shaun K.
dc.contributor.authorLi, James Y.H.
dc.contributor.authorBromleigh, Carrie
dc.contributor.authorEliseenkova, Anna V.
dc.contributor.authorIbrahimi, Omar A.
dc.contributor.authorLao, Zhimin
dc.contributor.authorZhang, Fuming
dc.contributor.authorLinhardt, Robert J.
dc.contributor.authorJoyner, Alexandra L.
dc.contributor.authorMohammadi, Moosa
dc.date2006
dc.date.accessioned2022-06-27T16:14:48Z
dc.date.available2022-06-27T16:14:48Z
dc.date.issued2006-01-15
dc.identifier.citationStructural Basis by which Alternative Splicing Modulates the Organizer Activity of FGF8 in the Brain, S. K. Olsen, J. Y. H. Li, C. Bromleigh, A. V. Eliseenkova, O. A. Ibrahimi, Z. Lao, F. Zhang, R. J. Linhardt, A. L. Joyner, Moosa Mohammadi, Genes and Development, 20, 185-198, 2006.
dc.identifier.issn15495477
dc.identifier.issn8909369
dc.identifier.urihttps://doi.org/10.1101/gad.1365406
dc.identifier.urihttps://hdl.handle.net/20.500.13015/5770
dc.descriptionGenes and Development, 20, 185-198
dc.descriptionNote : if this item contains full text it may be a preprint, author manuscript, or a Gold OA copy that permits redistribution with a license such as CC BY. The final version is available through the publisher’s platform.
dc.description.abstractTwo of the four human FGF8 splice isoforms, FGF8a and FGF8b, are expressed in the mid-hindbrain region during development. Although the only difference between these isoforms is the presence of an additional 11 amino acids at the N terminus of FGF8b, these isoforms possess remarkably different abilities to pattern the midbrain and anterior hindbrain. To reveal the structural basis by which alternative splicing modulates the organizing activity of FGF8, we solved the crystal structure of FGF8b in complex with the “c” splice isoform of FGF receptor 2 (FGFR2c). Using surface plasmon resonance (SPR), we also characterized the receptor-binding specificity of FGF8a and FGF8b, the “b” isoform of FGF17 (FGF17b), and FGF18. The FGF8b-FGFR2c structure shows that alternative splicing permits a single additional contact between phenylalanine 32 (F32) of FGF8b and a hydrophobic groove within Ig domain 3 of the receptor that is also present in FGFR1c, FGFR3c, and FGFR4. Consistent with the structure, mutation of F32 to alanine reduces the affinity of FGF8b toward all these receptors to levels characteristic of FGF8a. More importantly, analysis of the mid-hindbrain patterning ability of the FGF8bF32A mutant in chick embryos and murine midbrain explants shows that this mutation functionally converts FGF8b to FGF8a. Moreover, our data suggest that the intermediate receptor-binding affinities of FGF17b and FGF18, relative to FGF8a and FGF8b, also account for the distinct patterning abilities of these two ligands. We also show that the mode of FGF8 receptor-binding specificity is distinct from that of other FGFs and provide the first biochemical evidence for a physiological FGF8b-FGFR1c interaction during mid-hindbrain development. Consistent with the indispensable role of FGF8 in embryonic development, we show that the FGF8 mode of receptor binding appeared as early as in nematodes and has been preserved throughout evolution.
dc.description.sponsorshipNational Institute of General Medical Sciences
dc.languageen_US
dc.language.isoENG
dc.relation.ispartofThe Linhardt Research Labs Online Collection
dc.relation.ispartofRensselaer Polytechnic Institute, Troy, NY
dc.relation.ispartofGenes and Development
dc.relation.urihttps://harc.rpi.edu/
dc.subjectBiology
dc.subjectChemistry and chemical biology
dc.subjectChemical and biological engineering
dc.subjectBiomedical engineering
dc.titleStructural Basis by which Alternative Splicing Modulates the Organizer Activity of FGF8 in the Brain
dc.typeArticle
dcterms.isPartOfJournal
dcterms.isVersionOfhttps://doi.org/10.1101/gad.1365406
dc.rights.holderIn Copyright : this Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s). https://rightsstatements.org/page/InC/1.0/
dc.creator.identifierhttps://orcid.org/0000-0003-2219-5833
dc.relation.departmentThe Linhardt Research Labs.
dc.relation.departmentThe Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies (CBIS)
rpi.description.pages185-198
rpi.description.volume20


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