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Common structural traits for cystine knot domain of the TGFβ superfamily of proteins and three-fingered ectodomain of their cellular receptors

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Abstract

The transforming growth factor-β (TGFβ) superfamily of proteins and their receptors are crucial developmental factors for all metazoan organisms. Cystine-knot (CK) motif is a spatial feature of the TGFβ superfamily of proteins whereas the extra-cellular domains (ectodomains) of their respective receptors form three-fingered protein domain (TFPD), both stabilized by tight cystine networks. Analyses of multiple sequence alignments of these two domains encoded in various genomes revealed that the cystines forming the CK and TFPD folds are conserved, whereas the remaining polypeptide patches are diversified. Orthologues of the human TGFβs and their respective receptors expressed in diverse vertebrates retain high sequence conservation. Examination of 3D structures of various TGFβ factors bound to their receptors have revealed that the CK and TFPD domains display several similar spatial traits suggesting that these two different protein folds might have been acquired from a common ancestor.

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Abbreviations

TGFβ:

Transforming growth factor

GDF:

Growth/differentiation factor

GDNF:

Glial cell line-derived neurotrophic factor

AMH:

Anti-Mullerian hormone

PDGF:

Platelet-derived growth factor

LEFTY_A:

Endometrial bleeding associated factor

LEFTY_B:

Left–right determination factor B

PLGF:

Placental growth factor

CTGF:

Connective tissue growth factor

VEGF:

Vascular endothelial growth factor

CG:

Chorionic gonadotropin hormone

DAN:

Differential screening-selected gene aberrative in neuroblastoma

FSHβ:

Follicle-stimulating hormone

ActRIB:

Activin receptor type IB

ALK:

Activin receptor-like kinase

BMP:

Bone morphogenetic protein

BMPR:

BMP receptor

ASIP:

Agouti signaling protein

GPCR:

G protein-coupled receptor

TFPD:

Three-fingered protein domain

CK:

Cystine knot

ICK:

Inhibitor cystine knot

ECD:

Ectodomain

MSA:

Multiple sequence alignment

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Acknowledgments

We are indebted to SIMOPRO/iBiTecS/DSV/CEA for financial support.

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  1. Commissariat à l’Energie Atomique, Direction des Sciences du Vivant, Institut de Biologie et de Technologies de Saclay, Service d’Ingénierie Moléculaire des Protéines, Bat. 152, 91191, Gif-sur-Yvette, France

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Galat, A. Common structural traits for cystine knot domain of the TGFβ superfamily of proteins and three-fingered ectodomain of their cellular receptors. Cell. Mol. Life Sci. 68, 3437–3451 (2011). https://doi.org/10.1007/s00018-011-0643-4

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