Heterodimer-heterotetramer formation mediates enhanced sensor activity in a biophysical model for BMP signaling.

Numerous stages of organismal development rely on the cellular interpretation of gradients of secreted morphogens including members of the Bone Morphogenetic Protein (BMP) family through transmembrane receptors. Early gradients of BMPs drive dorsal/ventral patterning throughout the animal kingdom in...

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Autores principales:	Md Shahriar Karim, Aasakiran Madamanchi, James A Dutko, Mary C Mullins, David M Umulis
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/fa9f6624e9504963a9768fc815f313a3
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spelling	oai:doaj.org-article:fa9f6624e9504963a9768fc815f313a32021-12-02T19:57:42ZHeterodimer-heterotetramer formation mediates enhanced sensor activity in a biophysical model for BMP signaling.1553-734X1553-735810.1371/journal.pcbi.1009422https://doaj.org/article/fa9f6624e9504963a9768fc815f313a32021-09-01T00:00:00Zhttps://doi.org/10.1371/journal.pcbi.1009422https://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Numerous stages of organismal development rely on the cellular interpretation of gradients of secreted morphogens including members of the Bone Morphogenetic Protein (BMP) family through transmembrane receptors. Early gradients of BMPs drive dorsal/ventral patterning throughout the animal kingdom in both vertebrates and invertebrates. Growing evidence in Drosophila, zebrafish, murine and other systems suggests that BMP ligand heterodimers are the primary BMP signaling ligand, even in systems in which mixtures of BMP homodimers and heterodimers are present. Signaling by heterodimers occurs through a hetero-tetrameric receptor complex comprising of two distinct type one BMP receptors and two type II receptors. To understand the system dynamics and determine whether kinetic assembly of heterodimer-heterotetramer BMP complexes is favored, as compared to other plausible BMP ligand-receptor configurations, we developed a kinetic model for BMP tetramer formation based on current measurements for binding rates and affinities. We find that contrary to a common hypothesis, heterodimer-heterotetramer formation is not kinetically favored over the formation of homodimer-tetramer complexes under physiological conditions of receptor and ligand concentrations and therefore other mechanisms, potentially including differential kinase activities of the formed heterotetramer complexes, must be the cause of heterodimer-heterotetramer signaling primacy. Further, although BMP complex assembly favors homodimer and homomeric complex formation over a wide range of parameters, ignoring these signals and instead relying on the heterodimer improves the range of morphogen interpretation in a broad set of conditions, suggesting a performance advantage for heterodimer signaling in patterning multiple cell types in a gradient.Md Shahriar KarimAasakiran MadamanchiJames A DutkoMary C MullinsDavid M UmulisPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 17, Iss 9, p e1009422 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Md Shahriar Karim Aasakiran Madamanchi James A Dutko Mary C Mullins David M Umulis Heterodimer-heterotetramer formation mediates enhanced sensor activity in a biophysical model for BMP signaling.
description	Numerous stages of organismal development rely on the cellular interpretation of gradients of secreted morphogens including members of the Bone Morphogenetic Protein (BMP) family through transmembrane receptors. Early gradients of BMPs drive dorsal/ventral patterning throughout the animal kingdom in both vertebrates and invertebrates. Growing evidence in Drosophila, zebrafish, murine and other systems suggests that BMP ligand heterodimers are the primary BMP signaling ligand, even in systems in which mixtures of BMP homodimers and heterodimers are present. Signaling by heterodimers occurs through a hetero-tetrameric receptor complex comprising of two distinct type one BMP receptors and two type II receptors. To understand the system dynamics and determine whether kinetic assembly of heterodimer-heterotetramer BMP complexes is favored, as compared to other plausible BMP ligand-receptor configurations, we developed a kinetic model for BMP tetramer formation based on current measurements for binding rates and affinities. We find that contrary to a common hypothesis, heterodimer-heterotetramer formation is not kinetically favored over the formation of homodimer-tetramer complexes under physiological conditions of receptor and ligand concentrations and therefore other mechanisms, potentially including differential kinase activities of the formed heterotetramer complexes, must be the cause of heterodimer-heterotetramer signaling primacy. Further, although BMP complex assembly favors homodimer and homomeric complex formation over a wide range of parameters, ignoring these signals and instead relying on the heterodimer improves the range of morphogen interpretation in a broad set of conditions, suggesting a performance advantage for heterodimer signaling in patterning multiple cell types in a gradient.
format	article
author	Md Shahriar Karim Aasakiran Madamanchi James A Dutko Mary C Mullins David M Umulis
author_facet	Md Shahriar Karim Aasakiran Madamanchi James A Dutko Mary C Mullins David M Umulis
author_sort	Md Shahriar Karim
title	Heterodimer-heterotetramer formation mediates enhanced sensor activity in a biophysical model for BMP signaling.
title_short	Heterodimer-heterotetramer formation mediates enhanced sensor activity in a biophysical model for BMP signaling.
title_full	Heterodimer-heterotetramer formation mediates enhanced sensor activity in a biophysical model for BMP signaling.
title_fullStr	Heterodimer-heterotetramer formation mediates enhanced sensor activity in a biophysical model for BMP signaling.
title_full_unstemmed	Heterodimer-heterotetramer formation mediates enhanced sensor activity in a biophysical model for BMP signaling.
title_sort	heterodimer-heterotetramer formation mediates enhanced sensor activity in a biophysical model for bmp signaling.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/fa9f6624e9504963a9768fc815f313a3
work_keys_str_mv	AT mdshahriarkarim heterodimerheterotetramerformationmediatesenhancedsensoractivityinabiophysicalmodelforbmpsignaling AT aasakiranmadamanchi heterodimerheterotetramerformationmediatesenhancedsensoractivityinabiophysicalmodelforbmpsignaling AT jamesadutko heterodimerheterotetramerformationmediatesenhancedsensoractivityinabiophysicalmodelforbmpsignaling AT marycmullins heterodimerheterotetramerformationmediatesenhancedsensoractivityinabiophysicalmodelforbmpsignaling AT davidmumulis heterodimerheterotetramerformationmediatesenhancedsensoractivityinabiophysicalmodelforbmpsignaling
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Heterodimer-heterotetramer formation mediates enhanced sensor activity in a biophysical model for BMP signaling.

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