Adaptive protein divergence of BMP ligands takes place under developmental and evolutionary constraints

Tauscher, Petra; Gui, Jianian; Shimmi, Osamu

doi:10.1242/dev.130427

Cited by 7 publications

(8 citation statements)

References 49 publications

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“…Vertebrate and invertebrate BMP proteins and other members of the TGFβ superfamily each harbor several N -linked glycosylation sites, which have been shown to be glycosylated in many cases ( Groppe et al, 1998 ; Miyazono and Heldin, 1989 ; Tauscher et al, 2016 ). Various functional roles have been ascribed to N -glycans on these ligands, including enhancing receptor binding of BMP6 ( Saremba et al, 2008 ), keeping the TGFβ1 ligand in a latent state ( Miyazono and Heldin, 1989 ), and promoting inhibin (α/β) heterodimer formation at the expense of activin (β/β) homodimer formation ( Antenos et al, 2007 ).…”

Section: Discussionmentioning

confidence: 99%

Tissue-specific regulation of BMP signaling by Drosophila N-glycanase 1

Galeone

Han

Huang³

et al. 2017

eLife

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Mutations in the human N-glycanase 1 (NGLY1) cause a rare, multisystem congenital disorder with global developmental delay. However, the mechanisms by which NGLY1 and its homologs regulate embryonic development are not known. Here we show that Drosophila Pngl encodes an N-glycanase and exhibits a high degree of functional conservation with human NGLY1. Loss of Pngl results in developmental midgut defects reminiscent of midgut-specific loss of BMP signaling. Pngl mutant larvae also exhibit a severe midgut clearance defect, which cannot be fully explained by impaired BMP signaling. Genetic experiments indicate that Pngl is primarily required in the mesoderm during Drosophila development. Loss of Pngl results in a severe decrease in the level of Dpp homodimers and abolishes BMP autoregulation in the visceral mesoderm mediated by Dpp and Tkv homodimers. Thus, our studies uncover a novel mechanism for the tissue-specific regulation of an evolutionarily conserved signaling pathway by an N-glycanase enzyme.

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Section: Discussionmentioning

confidence: 99%

Tissue-specific regulation of BMP signaling by Drosophila N-glycanase 1

Galeone

Han

Huang³

et al. 2017

eLife

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“…The presence of glycans on extracellular proteins frequently alters the degree and quality of interactions with the extracellular matrix and with other secreted proteins (Tauscher et al, 2016;Dennis, 2017;Jayaprakash and Surolia, 2017). By analyzing the position of the putative Sog glycosylation sites one might gain insight to explain how glycan addition may modify Sog binding to interacting partners.…”

Section: Discussion N-linked Glycosylation Modulates Sog Functionmentioning

confidence: 99%

“…Addition of sugar side chains as a general mechanism to modify BMP function Several molecules that interact with BMP ligands are modified by glycans, and BMPs themselves are subject to glycan addition (Hang et al, 2014;Lowery et al, 2014;Tauscher et al, 2016). Among these molecules are proteoglycans (Guo and Wang, 2009;Häcker et al, 2005;Selleck, 2000), Tsg family proteins (Billington et al, 2011), as well as Sog/Chordin (Marqués et al, 1997).…”

Section: Glycans Control Extracellular Sog Levelsmentioning

confidence: 99%

N-linked glycosylation restricts the function of short gastrulation to bind and shuttle BMPs

et al. 2018

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Disorders of N-linked glycosylation are increasingly reported in the literature. However, the targets that are responsible for the associated developmental and physiological defects are largely unknown. Bone morphogenetic proteins (BMPs) act as highly dynamic complexes to regulate several functions during development. The range and strength of BMP activity depend on interactions with glycosylated protein complexes in the extracellular milieu. Here, we investigate the role of glycosylation for the function of the conserved extracellular BMP antagonist Short gastrulation (Sog). We identify conserved N-glycosylated sites and describe the effect of mutating these residues on BMP pathway activity in Drosophila. Functional analysis reveals that loss of individual Sog glycosylation sites enhances BMP antagonism and/or increases the spatial range of Sog effects in the tissue. Mechanistically, we provide evidence that N-terminal and stem glycosylation controls extracellular Sog levels and distribution. The identification of similar residues in vertebrate Chordin proteins suggests that N-glycosylation may be an evolutionarily conserved process that adds complexity to the regulation of BMP activity.

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“…The presence of glycans on extracellular proteins frequently alters the degree and quality of interactions with the extracellular matrix and with other secreted proteins (Tauscher et al, 2016, Dennis, 2017, Jayaprakash and Surolia, 2017. By analyzing the position of the putative Sog glycosylation sites one might gain insight to explain how glycan addition may regulate Sog binding to interacting partners.…”

Section: N-linked Glycosylation Modulates Sog Functionmentioning

confidence: 99%

“…Addition of sugar side chains as a general mechanism to regulate BMP function Several molecules that interact with BMP ligands are modified by glycans, and BMPs themselves are subject to glycan addition (Hang et al, 2014, Lowery et al, 2014, Tauscher et al, 2016. Among these molecules are proteoglycans (Guo and Wang, 2009, Häcker et al, 2005, Selleck, 2000, Tsg family proteins (Billington et al, 2011), as well as Sog/Chd (Marqués et al, 1997).…”

Section: Glycans Modulate Bmp Activity Range By Controlling Receptor-mentioning

confidence: 99%

N-linked glycosylation of the antagonist Short gastrulation increases the functional complexity of BMP signals

Negreiros¹,

Herszterg

K³

et al. 2018

Preprint

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AbstractDisorders of N-linked glycosylation are increasingly reported in the literature. However, targets responsible for the associated developmental and physiological defects are largely unknown. Bone Morphogenetic Proteins (BMPs) act as highly dynamic complexes to regulate several functions during development. The range and strength of BMP activity depend on interactions with glycosylated protein complexes in the extracellular milieu. Here we investigate the role of glycosylation for the function of the conserved extracellular BMP antagonist Short gastrulation (Sog). We identify conserved N-glycosylated sites and describe the effect of mutating these residues on BMP pathway activity in Drosophila. Functional analysis reveals that loss of individual Sog glycosylation sites enhances BMP antagonism and/or increases the spatial range of Sog effects in the tissue. Mechanistically, we provide evidence that N-terminal and stem glycosylation controls extracellular Sog levels and distribution. The identification of similar residues in vertebrate Chordin proteins suggests that N-glycosylation may be an evolutionarily conserved process that adds complexity to the regulation of BMP activity.Summary StatementN-glycosylation restricts the function of Short gastrulation during Drosophila development by controlling the amount of extracellular protein. This adds another layer of complexity to regulation of Bone Morphogenetic Protein signals.

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Adaptive protein divergence of BMP ligands takes place under developmental and evolutionary constraints

Cited by 7 publications

References 49 publications

Tissue-specific regulation of BMP signaling by Drosophila N-glycanase 1

Tissue-specific regulation of BMP signaling by Drosophila N-glycanase 1

N-linked glycosylation restricts the function of short gastrulation to bind and shuttle BMPs

N-linked glycosylation of the antagonist Short gastrulation increases the functional complexity of BMP signals

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