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

Lin, Shyr-Yeu; Lerch, Thomas F.; Cook, Robert W.; Jardetzky, Theodore S.; Woodruff, Teresa K.

doi:10.1530/rep.1.01072

Cited by 125 publications

(79 citation statements)

References 104 publications

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“…This is explained by the wide reach of contact points of Noggin, which simultaneously masks both BMPR1 a and BMPR2 epitopes (42). This remarkable structural reach is conserved among BMP antagonists and might explain their lack of BMP specificity (50). While the binding interface of Noggin to BMP is about 1,400 Å 2 (42), the size of a VHH paratope is usually 700 Å 2 (51).…”

Section: Discussionmentioning

confidence: 99%

Effective Inhibition of Bone Morphogenetic Protein Function by Highly Specific Llama-Derived Antibodies

Calpe

Wagner

Khattabi³

et al. 2015

Molecular Cancer Therapeutics

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Bone morphogenetic proteins (BMP) have important but distinct roles in tissue homeostasis and disease, including carcinogenesis and tumor progression. A large number of BMP inhibitors are available to study BMP function; however, as most of these antagonists are promiscuous, evaluating specific effects of individual BMPs is not feasible. Because the oncogenic role of the different BMPs varies for each neoplasm, highly selective BMP inhibitors are required. Here, we describe the generation of three types of llama-derived heavy chain variable domains (VHH) that selectively bind to either BMP4, to BMP2 and 4, or to BMP2, 4, 5, and 6. These generated VHHs have high affinity to their targets and are able to inhibit BMP signaling. Epitope binning and docking modeling have shed light into the basis for their BMP specificity. As opposed to the wide structural reach of natural inhibitors, these small molecules target the grooves and pockets of BMPs involved in receptor binding. In organoid experiments, specific inhibition of BMP4 does not affect the activation of normal stem cells. Furthermore, in vitro inhibition of cancer-derived BMP4 noncanonical signals results in an increase of chemosensitivity in a colorectal cancer cell line. Therefore, because of their high specificity and low off-target effects, these VHHs could represent a therapeutic alternative for BMP4 þ malignancies.

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Section: Discussionmentioning

confidence: 99%

Effective Inhibition of Bone Morphogenetic Protein Function by Highly Specific Llama-Derived Antibodies

Calpe

Wagner

Khattabi³

et al. 2015

Molecular Cancer Therapeutics

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“…However, they accomplish this by different structural mechanisms (8,19,20). Noggin binds BMP ligands in a 1:1 ratio.…”

Section: Fs288 Binding To Heparin Is Notmentioning

confidence: 99%

“…TGF␤ superfamily members typically exist as covalently linked dimers and fall into three main sub-categories: TGF␤s, activins/inhibins/nodals, and bone morphogenetic proteins (BMPs) (8). Structurally, these proteins all share a cysteine-knot fold and signal by engaging type II and type I receptors (9).…”

mentioning

confidence: 99%

Structural and Biophysical Coupling of Heparin and Activin Binding to Follistatin Isoform Functions

Lerch

Shimasaki

Woodruff

et al. 2007

Journal of Biological Chemistry

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Follistatin (FS) regulates transforming growth factor-␤ superfamily ligands and is necessary for normal embryonic and ovarian follicle development. Follistatin is expressed as two splice variants (FS288 and FS315). Previous studies indicated differences in heparin binding between FS288 and FS315, potentially influencing the physiological functions and locations of these isoforms. We have determined the structure of the FS315-activin A complex and quantitatively compared heparin binding by the two isoforms. The FS315 complex structure shows that both isoforms inhibit activin similarly, but FS315 exhibits movements within follistatin domain 3 (FSD3) apparently linked to binding of the C-terminal extension. Surprisingly, the binding affinities of FS288 and FS315 for heparin are similar at lower ionic strengths with FS315 binding decreasing more sharply as a function of salt concentration. When bound to activin, FS315 binds heparin similarly to the FS288 isoform, consistent with the structure of the complex, in which the acidic residues of the C-terminal extension cannot interact with the heparin-binding site. Activin-induced binding of heparin is unique to the FS315 isoform and may stimulate clearance of FS315 complexes.Ligands of the transforming growth factor-␤ (TGF␤) 3 superfamily regulate a diverse set of cellular and physiological functions, including early embryonic development, cellular growth and proliferation, and reproduction (1-3). Activin A, a member of the TGF␤ superfamily, is necessary to the regulation of both the male and the female reproductive axes by stimulating the release of follicle-stimulating hormone from the pituitary (4, 5). Activin A also has other important physiological roles, because activin A-deficient mice die shortly after birth and exhibit multiple defects in craniofacial development (6, 7). Comparative studies of the similarities and differences between TGF␤ ligands have lead to a better understanding of the many physiological effects of this multipotent ligand superfamily.TGF␤ superfamily members typically exist as covalently linked dimers and fall into three main sub-categories: TGF␤s, activins/inhibins/nodals, and bone morphogenetic proteins (BMPs) (8). Structurally, these proteins all share a cysteine-knot fold and signal by engaging type II and type I receptors (9). Activin and BMPs bind to their type II receptors through a structural feature known as the "knuckle" region (10 -12). They have similar type I receptor binding sites on the concave surfaces of the molecule, which span both monomers of the ligands (13-16). Although specific ligand:receptor pairs have been characterized, multiple ligands share several receptors providing complexity and precise control to the system. The members of this superfamily are produced as prepro-proteins, and the pro-domain often regulates biological functions. In the absence of the pro-domain, TGF␤-1 and -2, as well as BMP-2, -4, and -7, can bind directly to the cell surface through heparin binding sites (17,18). This provides a mechanism f...

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“…These structures show that activin binds to its type II receptors through the 'knuckle' region, which is different from TGF-β, yet similar to that of BMPs (Lin et al, 2006). Surprisingly, activin was found to have flexibility about the dimer interface ( Fig.…”

Section: Structures and Signals That Regulate Local And Endocrinementioning

confidence: 93%

The structures that underlie normal reproductive function

Lerch¹,

Xu²,

Jardetzky³

et al. 2007

Molecular and Cellular Endocrinology

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The mechanisms and physiology of reproductive function have fascinated scientists throughout time. Recent cellular and molecular level structural studies have provided unprecedented insights into reproductive systems and signaling networks. This 'cutting edge' editorial provides a recent example in each of these areas, namely, the anatomical integrity of the follicle, the molecular structure of activin with its binding partners and the molecular regulation of inhibin. These three examples of structure informing function help explain reproductive health and may provide solutions to reproductive disease.

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

Cited by 125 publications

References 104 publications

Effective Inhibition of Bone Morphogenetic Protein Function by Highly Specific Llama-Derived Antibodies

Effective Inhibition of Bone Morphogenetic Protein Function by Highly Specific Llama-Derived Antibodies

Structural and Biophysical Coupling of Heparin and Activin Binding to Follistatin Isoform Functions

The structures that underlie normal reproductive function

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