@article{6b0ed8d8e3ac47aaa897f1e858d638cd,
title = "Structural Adaptation in Its Orphan Domain Engenders Betaglycan with an Alternate Mode of Growth Factor Binding Relative to Endoglin",
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.",
keywords = "SAXS, SPR, X-ray crystallography, betaglycan, cardiac development, cell signaling, cell surface receptor, co-receptor, endoglin, transforming growth factor beta (TGF-β)",
author = "Kim, {Sun Kyung} and Whitley, {Matthew J.} and Krzysiak, {Troy C.} and Hinck, {Cynthia S.} and Taylor, {Alexander B.} and Christian Zwieb and Byeon, {Chang Hyeock} and Xiaohong Zhou and Valent{\'i}n Mendoza and Fernando L{\'o}pez-Casillas and William Furey and Hinck, {Andrew P.}",
note = "Funding Information: The authors would like to thank Doowon Lee for assistance with the X-ray instrumentation, Mike Delk for assistance with the NMR instrumentation, Drs. Lixin Fan and Xiaobing Zuo for assistance with SAXS data collection, Drs. Christopher Barnes and Guillermo Calero for their assistance with structure determination of rBG O , and Dr. {\L}ukasz Wieteska for providing valuable comments on the manuscript. This research was supported by the NIH ( GM58670 and CA172886 ), the US Department of Defense ( DoD W81XWH-17-1-0429 ), and the University of Pittsburgh Vascular Medicine Institute . S.K.K. was supported by training grants provided by CPRIT ( RP1450105 ) and the AHA ( 15PRE25550015 ), and F.L.-C. is supported by CONACYT ( 254046 ). X-ray diffraction data were collected at the SER-CAT 22-ID beamline at the Advanced Photon Source (APS), Argonne National Laboratory (ANL). SER-CAT is supported by its member institutions and equipment grants ( RR25528 and RR028976 ) from the NIH. SAXS data were collected through the SAXS core facility of Center for Cancer Research , National Cancer Institute (NCI), which utilized ANL APS beamline 12-ID-B under PUP-24152. Molecular graphics and analyses were performed with UCSF Chimera, which is developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, and supported by NIGMS P41-GM103311 . The X-ray Crystallography Core Laboratory at UT Health Science Center at San Antonio is supported by the Office of the Vice President for Research and the Mays Cancer Center , the center home to the UT Health San Antonio MD Anderson Cancer Center (NIH P30 CA054174 ). Funding Information: The authors would like to thank Doowon Lee for assistance with the X-ray instrumentation, Mike Delk for assistance with the NMR instrumentation, Drs. Lixin Fan and Xiaobing Zuo for assistance with SAXS data collection, Drs. Christopher Barnes and Guillermo Calero for their assistance with structure determination of rBGO, and Dr. ?ukasz Wieteska for providing valuable comments on the manuscript. This research was supported by the NIH (GM58670 and CA172886), the US Department of Defense (DoD W81XWH-17-1-0429), and the University of Pittsburgh Vascular Medicine Institute. S.K.K. was supported by training grants provided by CPRIT (RP1450105) and the AHA (15PRE25550015), and F.L.-C. is supported by CONACYT (254046). X-ray diffraction data were collected at the SER-CAT 22-ID beamline at the Advanced Photon Source (APS), Argonne National Laboratory (ANL). SER-CAT is supported by its member institutions and equipment grants (RR25528 and RR028976) from the NIH. SAXS data were collected through the SAXS core facility of Center for Cancer Research, National Cancer Institute (NCI), which utilized ANL APS beamline 12-ID-B under PUP-24152. Molecular graphics and analyses were performed with UCSF Chimera, which is developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, and supported by NIGMS P41-GM103311. The X-ray Crystallography Core Laboratory at UT Health Science Center at San Antonio is supported by the Office of the Vice President for Research and the Mays Cancer Center, the center home to the UT Health San Antonio MD Anderson Cancer Center (NIH P30 CA054174). S.K.K. crystallized zfBGO and collected and analyzed the X-ray data, with assistance from M.J.W. W.F. X.Z. A.B.T. and A.P.H. S.K.K. performed the accompanying functional studies, with assistance from C.-H.B. S.K.K. produced all the coding constructs and expressed and purified the protein, with assistance from C.S.H. T.C.K. C.Z. C.-H.B. V.M. F.L.-C. and A.P.H. S.K.K. and A.P.H. wrote the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 Elsevier Ltd",
year = "2019",
month = sep,
day = "3",
doi = "10.1016/j.str.2019.06.010",
language = "English (US)",
volume = "27",
pages = "1427--1442.e4",
journal = "Structure with Folding & design",
issn = "0969-2126",
publisher = "Cell Press",
number = "9",
}