Structural Adaptation in Its Orphan Domain Engenders Betaglycan with an Alternate Mode of Growth Factor Binding Relative to Endoglin

Sun Kyung Kim, Matthew J. Whitley, Troy C. Krzysiak, Cynthia S. Hinck, Alexander B. Taylor, Christian Zwieb, Chang Hyeock Byeon, Xiaohong Zhou, Valentín Mendoza, Fernando López-Casillas, William Furey, Andrew P. Hinck

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Betaglycan (BG) and endoglin (ENG), homologous co-receptors of the TGF-β family, potentiate the signaling activity of TGF-β2 and inhibin A, and BMP-9 and BMP-10, respectively. BG exists as monomer and forms 1:1 growth factor (GF) complexes, while ENG exists as a dimer and forms 2:1 GF complexes. Herein, the structure of the BG orphan domain (BGO) reveals an insertion that blocks the region that the endoglin orphan domain (ENGO) uses to bind BMP-9, preventing it from binding in the same manner. Using binding studies with domain-deleted forms of TGF-β and BGO, as well as small-angle X-ray scattering data, BGO is shown to bind its cognate GF in an entirely different manner compared with ENGO. The alternative interfaces likely engender BG and ENG with the ability to selectively bind and target their cognate GFs in a unique temporal-spatial manner, without interfering with one another or other TGF-β family GFs. Kim et al. determine the structure of the betaglycan orphan domain (BGO) and show that the edge β strand that endoglin uses to bind its cognate growth factor is blocked by an insertion. Binding studies and SAXS show that BGO binds its cognate growth factor differently compared with endoglin.

Original languageEnglish (US)
Pages (from-to)1427-1442.e4
JournalStructure
Volume27
Issue number9
DOIs
StatePublished - Sep 3 2019

Keywords

  • SAXS
  • SPR
  • X-ray crystallography
  • betaglycan
  • cardiac development
  • cell signaling
  • cell surface receptor
  • co-receptor
  • endoglin
  • transforming growth factor beta (TGF-β)

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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    Kim, S. K., Whitley, M. J., Krzysiak, T. C., Hinck, C. S., Taylor, A. B., Zwieb, C., Byeon, C. H., Zhou, X., Mendoza, V., López-Casillas, F., Furey, W., & Hinck, A. P. (2019). Structural Adaptation in Its Orphan Domain Engenders Betaglycan with an Alternate Mode of Growth Factor Binding Relative to Endoglin. Structure, 27(9), 1427-1442.e4. https://doi.org/10.1016/j.str.2019.06.010