Crystal structure of recombinant human growth and differentiation factor 5: Evidence for interaction of the type I and type II receptor-binding sites

Schreuder, Herman; Liesum, A.; Pohl, J; Kruse, Michael; Koyama, Masayoshi

doi:10.1016/j.bbrc.2005.02.078

Cited by 51 publications

(52 citation statements)

References 26 publications

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“…At the N terminus, fingers 1 and 2 are antiparallel, with finger 2 leading to a general helix 'wrist' region, followed by antiparallel fingers 3 and 4 and the C terminus. Since then, the structures of several other TGF-b ligands have been elucidated, including TGF-b1 (Hinck et al 1996), TGF-b3 (Mittl et al 1996, Hart et al 2002, BMP-2 (Scheufler et al 1999, Kirsch et al 2000b, Allendorph et al 2006, BMP-7 (Griffith et al 1996, Greenwald et al 2003, BMP-9 (Brown et al 2005), GDF-5 (Nickel et al 2005, Schreuder et al 2005, and activin (Thompson et al 2003, Greenwald et al 2004, Harrington et al 2006, further confirming the identity of the TGF-b fold.…”

Section: Structure Of Tgf-b Superfamily Ligands and Receptorsmentioning

confidence: 85%

The structural basis of TGF-β, bone morphogenetic protein, and activin ligand binding

Lin¹,

Lerch²,

Cook³

et al. 2006

Reproduction

124

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The transforming growth factor-b (TGF-b) superfamily is a large group of structurally related growth factors that play prominent roles in a variety of cellular processes. The importance and prevalence of TGF-b signaling are also reflected by the complex network of check points that exist along the signaling pathway, including a number of extracellular antagonists and membranelevel signaling modulators. Recently, a number of important TGF-b crystal structures have emerged and given us an unprecedented clarity on several aspects of the signal transduction process. This review will highlight these latest advances and present our current understanding on the mechanisms of specificity and regulation on TGF-b signaling outside the cell.

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Section: Structure Of Tgf-b Superfamily Ligands and Receptorsmentioning

confidence: 85%

The structural basis of TGF-β, bone morphogenetic protein, and activin ligand binding

Lin¹,

Lerch²,

Cook³

et al. 2006

Reproduction

124

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“…This includes a number of growth factors (platelet-derived growth factor, vascular endothelial growth factor, glial cell linederived neurotrophic factor, transforming growth factor-␤2, brain-derived neurotrophic factor, BMP-7, NT3, activin, GDF-5 and Artemin), the cytokine IL17F, the inhibitory protein Noggin, the glycoprotein hormone chorionic gonadotropin and a coagulation factor) (47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61). With the exception of the coagulation factor, all of these cystine-knot proteins are known to form functional homo-or heterodimers; however, there is no evidence to suggest that sclerostin dimerizes.…”

Section: Resultsmentioning

confidence: 99%

Characterization of the Structural Features and Interactions of Sclerostin

Veverka

Henry

Slocombe

et al. 2009

Journal of Biological Chemistry

211

109

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The secreted glycoprotein sclerostin has recently emerged as a key negative regulator of Wnt signaling in bone and has stimulated considerable interest as a potential target for therapeutics designed to treat conditions associated with low bone mass, such as osteoporosis. We have determined the structure of sclerostin, which resulted in the identification of a previously unknown binding site for heparin, suggestive of a functional role in localizing sclerostin to the surface of target cells. We have also mapped the interaction site for an antibody that blocks the inhibition of Wnt signaling by sclerostin. This shows minimal overlap with the heparin binding site and highlights a key role for this region of sclerostin in protein interactions associated with the inhibition of Wnt signaling. The conserved N-and C-terminal arms of sclerostin were found to be unstructured, highly flexible, and unaffected by heparin binding, which suggests a role in stabilizing interactions with target proteins.

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“…The knuckle epitope is a common binding interface for TGF␤ superfamily ligands. Activins, BMPs and growth and differentiation factors bind their type II receptors at this site (8,12,31). In addition, follistatin antagonizes the actions of multiple TGF␤ ligands by binding to this region and preventing ligand access to their signaling receptors (7,32,33).…”

Section: Discussionmentioning

confidence: 99%

Suppression of Inhibin A Biological Activity by Alterations in the Binding Site for Betaglycan

Makanji

Walton²,

Wilce

et al. 2008

Journal of Biological Chemistry

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Inhibins A and B negatively regulate the production and secretion of follicle-stimulating hormone from the anterior pituitary, control ovarian follicle development and steroidogenesis, and act as tumor suppressors in the gonads. Inhibins regulate these reproductive events by forming high affinity complexes with betaglycan and activin or bone morphogenetic protein type II receptors. In this study, the binding site of inhibin A for betaglycan was characterized using inhibin A mutant proteins. An epitope for high affinity betaglycan binding was detected spanning the outer convex surface of the inhibin ␣-subunit. Inhibin A and inhibin B, members of the TGF␤ 2 superfamily, are essential regulatory factors in mammalian reproduction. Their expression is critical for the regulation of fertility based on their dual inhibitory actions on follicle-stimulating hormone (FSH) secretion by the pituitary (1, 2) and gametogenesis in the gonads (3, 4). It is recognized that inhibins regulate these reproductive events by inhibiting the stimulatory actions of the structurally related proteins, activins (5, 6). Inhibins are heterodimers of an 18-kDa ␣-subunit disulfide-linked to one of two 13-kDa ␤-subunits (␤A and ␤B), resulting in inhibin A or inhibin B, respectively. Each activin is composed of two ␤-subunits; ␤A-␤A (activin A), ␤A-␤B (activin AB), and ␤B-␤B (activin B). Although the inhibin A and inhibin B crystal structures have not been determined, based upon sequence identity it is expected that the ␤-subunits would retain a similar conformation to that observed in the activin A dimer (7). Thus, within either ␤-subunit, two pairs of anti-parallel ␤-strands, forming a short and a long "finger," stretch outward from the cysteine knot core of the monomer. At the base of the fingers, each ␤-subunit forms an ␣-helix, which together with the prehelix loop, generates the "wrist" region of the molecule (8).An interchain disulfide bond between Cys 80 of the ␤A-subunit (Cys 79 of the ␤B-subunit) and Cys 95 of the ␣-subunit covalently connects the two chains of the inhibin dimers. In humans, unlike other species, two molecular mass isoforms of mature inhibin A and B (31 and 34 kDa) have been identified (9). This molecular mass heterogeneity is due to the presence of two N-linked glycosylation sites at Asn 36 and Asn 70 of the ␣-subunit. Asn 36 is always glycosylated (producing 31-kDa inhibin A or B), whereas glycosylation of Asn 70 is differentially regulated (producing 34-kDa inhibin A or B) (10). The presence of a second carbohydrate moiety significantly reduces the biological activity of inhibin A (9), suggesting that human inhibins may be under more stringent control than inhibins from other species.Inhibins exert their biological effects by antagonizing the actions of TGF␤ ligands that utilize activin (ActRII/IIB) or BMP (BMPRII) type II receptors as part of their signaling complex (11). The inhibin residues involved in binding to the type II receptors can be inferred from the crystal structure of activin A bound to ActRIIB (12). I...

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Crystal structure of recombinant human growth and differentiation factor 5: Evidence for interaction of the type I and type II receptor-binding sites

Cited by 51 publications

References 26 publications

The structural basis of TGF-β, bone morphogenetic protein, and activin ligand binding

The structural basis of TGF-β, bone morphogenetic protein, and activin ligand binding

Characterization of the Structural Features and Interactions of Sclerostin

Suppression of Inhibin A Biological Activity by Alterations in the Binding Site for Betaglycan

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