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Molecular Basis of Interchain Disulf...

Schwartze, Tristin Alexander,

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Molecular Basis of Interchain Disulfide-Bond Formation in BMP-9 and BMP-10 /

Record Type:	Electronic resources : Monograph/item
Title/Author:	Molecular Basis of Interchain Disulfide-Bond Formation in BMP-9 and BMP-10 // Tristin Alexander Schwartze.
Author:	Schwartze, Tristin Alexander,
Description:	1 electronic resource (226 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 86-12, Section: B.
Contained By:	Dissertations Abstracts International86-12B.
Subject:	Molecular biology. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31841430
ISBN:	9798315788690

Molecular Basis of Interchain Disulfide-Bond Formation in BMP-9 and BMP-10 /
Schwartze, Tristin Alexander,

Molecular Basis of Interchain Disulfide-Bond Formation in BMP-9 and BMP-10 /Tristin Alexander Schwartze. - 1 electronic resource (226 pages)

Source: Dissertations Abstracts International, Volume: 86-12, Section: B.

BMP-9 and BMP-10 are TGF-β family signaling ligands naturally secreted into blood. They act on endothelial cells and are required for proper development and maintenance of the vasculature. In hereditary hemorrhagic telangiectasia, regulation is disrupted due to mutations in the BMP-9/10 pathway, namely in the type I receptor ALK1 or the co-receptor endoglin. It has been demonstrated that BMP-9/10 heterodimers are the most abundant signaling species in the blood, but it is unclear how they form. Unlike other ligands of the TGF-β family, BMP-9 and -10 are each secreted as a mixture of disulfide-linked homodimers and monomers. Here, we show that the monomers are secreted in a cysteinylated form that crystallizes as a noncovalent homodimer. Despite this, monomers do not self-associate at micromolar or lower concentrations and have reduced signaling potency compared to disulfide-linked dimers. Using protein crystallography, we show that the interchain disulfide of the BMP-9 homodimer adopts a highly strained syn-periplanar conformation. Hence, geometric strain across the interchain disulfide is responsible for the infrequent interchain disulfide-bond formation, not the cysteinylation. Additionally, we show that interchain disulfide-bond formation occurs less in BMP-9 than BMP-10 and these frequencies can be reversed by swapping residues between BMP-9 and BMP-10 near the interchain disulfide that form attractive interactions with the opposing protomer in BMP-10. Finally, this thesis touches on work investigating parasite and synthetic proteins that bind the type-II TGF-β receptor TβRII as they may grant insights into approaches to treat hereditary hemorrhagic telangiectasia.

English

ISBN: 9798315788690Subjects--Topical Terms:

517296
Molecular biology.
Subjects--Index Terms:

Bone morphogenetic protein

Molecular Basis of Interchain Disulfide-Bond Formation in BMP-9 and BMP-10 /
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520 $a BMP-9 and BMP-10 are TGF-β family signaling ligands naturally secreted into blood. They act on endothelial cells and are required for proper development and maintenance of the vasculature. In hereditary hemorrhagic telangiectasia, regulation is disrupted due to mutations in the BMP-9/10 pathway, namely in the type I receptor ALK1 or the co-receptor endoglin. It has been demonstrated that BMP-9/10 heterodimers are the most abundant signaling species in the blood, but it is unclear how they form. Unlike other ligands of the TGF-β family, BMP-9 and -10 are each secreted as a mixture of disulfide-linked homodimers and monomers. Here, we show that the monomers are secreted in a cysteinylated form that crystallizes as a noncovalent homodimer. Despite this, monomers do not self-associate at micromolar or lower concentrations and have reduced signaling potency compared to disulfide-linked dimers. Using protein crystallography, we show that the interchain disulfide of the BMP-9 homodimer adopts a highly strained syn-periplanar conformation. Hence, geometric strain across the interchain disulfide is responsible for the infrequent interchain disulfide-bond formation, not the cysteinylation. Additionally, we show that interchain disulfide-bond formation occurs less in BMP-9 than BMP-10 and these frequencies can be reversed by swapping residues between BMP-9 and BMP-10 near the interchain disulfide that form attractive interactions with the opposing protomer in BMP-10. Finally, this thesis touches on work investigating parasite and synthetic proteins that bind the type-II TGF-β receptor TβRII as they may grant insights into approaches to treat hereditary hemorrhagic telangiectasia.
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650 4 $a Biochemistry. $3 518028
650 4 $a Biophysics. $3 518360
653 $a Bone morphogenetic protein
653 $a Crystallography
653 $a Radiation sensitivity
653 $a Strained disulfide
653 $a Hemorrhagic telangiectasia
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