9fkp

Zebrafish Betaglycan Orphan Domain (zfBGo) in complex with TGF-b1 and extracellular domain of TGFBRII

Structural highlights

9fkp is a 5 chain structure with sequence from Danio rerio and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.72Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

TGFB1_HUMAN Defects in TGFB1 are the cause of Camurati-Engelmann disease (CE) [MIM:131300; also known as progressive diaphyseal dysplasia 1 (DPD1). CE is an autosomal dominant disorder characterized by hyperostosis and sclerosis of the diaphyses of long bones. The disease typically presents in early childhood with pain, muscular weakness and waddling gait, and in some cases other features such as exophthalmos, facial paralysis, hearing difficulties and loss of vision.^[1] ^[2] ^[3] ^[4] ^[5]

Function

TGFB1_HUMAN Multifunctional protein that controls proliferation, differentiation and other functions in many cell types. Many cells synthesize TGFB1 and have specific receptors for it. It positively and negatively regulates many other growth factors. It plays an important role in bone remodeling as it is a potent stimulator of osteoblastic bone formation, causing chemotaxis, proliferation and differentiation in committed osteoblasts.

Publication Abstract from PubMed

Betaglycan (BG) is a transmembrane co-receptor of the transforming growth factor-beta (TGF-beta) family of signaling ligands. It is essential for embryonic development, tissue homeostasis and fertility in adults. It functions by enabling binding of the three TGF-beta isoforms to their signaling receptors and is additionally required for inhibin A (InhA) activity. Despite its requirement for the functions of TGF-betas and InhA in vivo, structural information explaining BG ligand selectivity and its mechanism of action is lacking. Here, we determine the structure of TGF-beta bound both to BG and the signaling receptors, TGFBR1 and TGFBR2. We identify key regions responsible for ligand engagement, which has revealed binding interfaces that differ from those described for the closely related co-receptor of the TGF-beta family, endoglin, thus demonstrating remarkable evolutionary adaptation to enable ligand selectivity. Finally, we provide a structural explanation for the hand-off mechanism underlying TGF-beta signal potentiation.

Structures of TGF-beta with betaglycan and signaling receptors reveal mechanisms of complex assembly and signaling.,Wieteska L, Taylor AB, Punch E, Coleman JA, Conway IO, Lin YF, Byeon CH, Hinck CS, Krzysiak T, Ishima R, Lopez-Casillas F, Cherepanov P, Bernard DJ, Hill CS, Hinck AP Nat Commun. 2025 Feb 26;16(1):1778. doi: 10.1038/s41467-025-56796-9. PMID:40011426^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Kinoshita A, Saito T, Tomita H, Makita Y, Yoshida K, Ghadami M, Yamada K, Kondo S, Ikegawa S, Nishimura G, Fukushima Y, Nakagomi T, Saito H, Sugimoto T, Kamegaya M, Hisa K, Murray JC, Taniguchi N, Niikawa N, Yoshiura K. Domain-specific mutations in TGFB1 result in Camurati-Engelmann disease. Nat Genet. 2000 Sep;26(1):19-20. PMID:10973241 doi:10.1038/79128
↑ Janssens K, Gershoni-Baruch R, Guanabens N, Migone N, Ralston S, Bonduelle M, Lissens W, Van Maldergem L, Vanhoenacker F, Verbruggen L, Van Hul W. Mutations in the gene encoding the latency-associated peptide of TGF-beta 1 cause Camurati-Engelmann disease. Nat Genet. 2000 Nov;26(3):273-5. PMID:11062463 doi:10.1038/81563
↑ Janssens K, ten Dijke P, Ralston SH, Bergmann C, Van Hul W. Transforming growth factor-beta 1 mutations in Camurati-Engelmann disease lead to increased signaling by altering either activation or secretion of the mutant protein. J Biol Chem. 2003 Feb 28;278(9):7718-24. Epub 2002 Dec 18. PMID:12493741 doi:10.1074/jbc.M208857200
↑ McGowan NW, MacPherson H, Janssens K, Van Hul W, Frith JC, Fraser WD, Ralston SH, Helfrich MH. A mutation affecting the latency-associated peptide of TGFbeta1 in Camurati-Engelmann disease enhances osteoclast formation in vitro. J Clin Endocrinol Metab. 2003 Jul;88(7):3321-6. PMID:12843182
↑ Kinoshita A, Fukumaki Y, Shirahama S, Miyahara A, Nishimura G, Haga N, Namba A, Ueda H, Hayashi H, Ikegawa S, Seidel J, Niikawa N, Yoshiura K. TGFB1 mutations in four new families with Camurati-Engelmann disease: confirmation of independently arising LAP-domain-specific mutations. Am J Med Genet A. 2004 May 15;127A(1):104-7. PMID:15103729 doi:10.1002/ajmg.a.20671
↑ Wieteska Ł, Taylor AB, Punch E, Coleman JA, Conway IO, Lin YF, Byeon CH, Hinck CS, Krzysiak T, Ishima R, López-Casillas F, Cherepanov P, Bernard DJ, Hill CS, Hinck AP. Structures of TGF-β with betaglycan and signaling receptors reveal mechanisms of complex assembly and signaling. Nat Commun. 2025 Feb 26;16(1):1778. PMID:40011426 doi:10.1038/s41467-025-56796-9

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OCA

[1] Kinoshita A, Saito T, Tomita H, Makita Y, Yoshida K, Ghadami M, Yamada K, Kondo S, Ikegawa S, Nishimura G, Fukushima Y, Nakagomi T, Saito H, Sugimoto T, Kamegaya M, Hisa K, Murray JC, Taniguchi N, Niikawa N, Yoshiura K. Domain-specific mutations in TGFB1 result in Camurati-Engelmann disease. Nat Genet. 2000 Sep;26(1):19-20. PMID:10973241 doi:10.1038/79128

[2] Janssens K, Gershoni-Baruch R, Guanabens N, Migone N, Ralston S, Bonduelle M, Lissens W, Van Maldergem L, Vanhoenacker F, Verbruggen L, Van Hul W. Mutations in the gene encoding the latency-associated peptide of TGF-beta 1 cause Camurati-Engelmann disease. Nat Genet. 2000 Nov;26(3):273-5. PMID:11062463 doi:10.1038/81563

[3] Janssens K, ten Dijke P, Ralston SH, Bergmann C, Van Hul W. Transforming growth factor-beta 1 mutations in Camurati-Engelmann disease lead to increased signaling by altering either activation or secretion of the mutant protein. J Biol Chem. 2003 Feb 28;278(9):7718-24. Epub 2002 Dec 18. PMID:12493741 doi:10.1074/jbc.M208857200

[4] McGowan NW, MacPherson H, Janssens K, Van Hul W, Frith JC, Fraser WD, Ralston SH, Helfrich MH. A mutation affecting the latency-associated peptide of TGFbeta1 in Camurati-Engelmann disease enhances osteoclast formation in vitro. J Clin Endocrinol Metab. 2003 Jul;88(7):3321-6. PMID:12843182

[5] Kinoshita A, Fukumaki Y, Shirahama S, Miyahara A, Nishimura G, Haga N, Namba A, Ueda H, Hayashi H, Ikegawa S, Seidel J, Niikawa N, Yoshiura K. TGFB1 mutations in four new families with Camurati-Engelmann disease: confirmation of independently arising LAP-domain-specific mutations. Am J Med Genet A. 2004 May 15;127A(1):104-7. PMID:15103729 doi:10.1002/ajmg.a.20671

[6] Wieteska Ł, Taylor AB, Punch E, Coleman JA, Conway IO, Lin YF, Byeon CH, Hinck CS, Krzysiak T, Ishima R, López-Casillas F, Cherepanov P, Bernard DJ, Hill CS, Hinck AP. Structures of TGF-β with betaglycan and signaling receptors reveal mechanisms of complex assembly and signaling. Nat Commun. 2025 Feb 26;16(1):1778. PMID:40011426 doi:10.1038/s41467-025-56796-9

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9fkp

Zebrafish Betaglycan Orphan Domain (zfBGo) in complex with TGF-b1 and extracellular domain of TGFBRII

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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