Structural Biology and Evolution of the TGF-β Family

Abstract

We review the evolution and structure of members of the transforming growth factor β (TGF-β) family, antagonistic or agonistic modulators, and receptors that regulate TGF-β signaling in extracellular environments. The growth factor (GF) domain common to all family members and many of their antagonists evolved from a common cystine knot growth factor (CKGF) domain. The CKGF superfamily comprises six distinct families in primitive metazoans, including the TGF-β and Dan families. Compared with Wnt/Frizzled and Notch/Delta families that also specify body axes, cell fate, tissues, and other families that contain CKGF domains that evolved in parallel, the TGF-β family was the most fruitful in evolution. Complexes between the prodomains and GFs of the TGF-β family suggest a new paradigm for regulating GF release by conversion from closed- to open-arm procomplex conformations. Ternary complexes of the final step in extracellular signaling show how TGF-β GF dimers bind type I and type II receptors on the cell surface, and enable understanding of much of the specificity and promiscuity in extracellular signaling. However, structures suggest that when GFs bind repulsive guidance molecule (RGM) family coreceptors, type I receptors do not bind until reaching an intracellular, membrane-enveloped compartment, blurring the line between extra- and intracellular signaling. Modulator protein structures show how structurally diverse antagonists including follistatins, noggin, and members of the chordin family bind GFs to regulate signaling; complexes with the Dan family remain elusive. Much work is needed to understand how these molecular components assemble to form signaling hubs in extracellular environments in vivo.

A Novel GDF6 Mutation in a Family with Multiple Synostoses Syndrome without Hearing Loss

“…The GDF6 (BMP13) structure has not yet been reported, but since GDF6 is a paralogue of GDF5 and BMP7 (i.e., have virtually identical tertiary structures) [Hinck et al, 2016] with high sequence identity in the C-terminal TGFβ domain, structural data of the BMP7-NOG complex ( Fig. 3 a, PDB ID:1M4U) and the GDF5-BMPR1B complex ( Fig.…”

An engineered transforming growth factor β (TGF-β) monomer that functions as a dominant negative to block TGF-β signaling

“…Their overall structures are similar and consist of two cystine-knotted monomers tethered together by a single inter-chain disulfide bond (1). They coordinate wound healing, modulate immune cell function, maintain the extracellular matrix, and regulate epithelial and endothelial cell growth and differentiation (2).…”

“…This approach offers several potential advantages over existing therapies. Relative to kinase inhibitors, engineered GFs would be expected to have much higher specificity, especially if they function by binding and blocking T␤RII, which is known to only bind and transduce signals for TGF-␤1, -␤2, and -␤3, but not other TGF-␤ family GFs (1,30). Another potential advantage over kinase inhibitors is increased bioavailability because, unlike the kinase inhibitors, engineered GFs would not have to cross the plasma membrane to reach their target.…”

Atypical interactions of integrin α V β 8 with pro-TGF-β1

“…However, integrin binding alone is not sufficient for latent TGF-β activation by α V β 6 ; force is also required. Experiments suggest that tensile force is transmitted from the cytoskeleton to the integrin, is resisted by anchorage of TGF-β1 in the extracellular matrix or on cell surfaces, and results in distortion of prodomain straitjacket elements that loosely surround the growth factor followed by release of the growth factor (7,8). In some systems, activation of TGF-β1 by α V β 8 is dependent on matrix metalloprotease (9) whereas in others activation requires linkage of pro-TGF-β1 to a surface, suggesting a role for force exertion (10).…”