Homo Sapiens
Transforming Growth Factor, Beta-III

Jonathan Sun '16 &

Stephanie Cordonnier '15


I. Introduction

Transforming Growth Factor- Beta III (TGF-B3), a subset of a cytokine family, is responsible for a plethora of functions including cellular proliferation, embryogenesis, immune system regulation, and differentiation. Recent experiments have shown TGF-B3 may aid in tissue regeneration through cell homing. TGF-B3 utilizes cell homing by recruiting endogenous host cells, including stem and progenitor cells, from several sources and causing them to interact with one another. Cell homing may be a solution to barriers faced in alternate methods such as cell delivery which can cause problems such as immune rejection and pathogen transmission. Two transmembrane constitutively-active serine/threonine receptor kinases, ectodomain TGF-B type I and II (ecTBR1 and ecTBR2), are bound by the ligand TGF-B3 to initiate this signaling.  

II. TGF-B3 Structure

TGF-B3 is a homodimer, and its genetic sequence is highly conserved across species. There are six beta sheets and three alpha helices in each .

The subunit forms a hand shape with the beta sheets creating the knuckle, thumb, and fingers one-four. The palm of the hand is formed by a disulfide core which is created through a knot of three . Bridges between and create a large enough ring to allow the third bridge, , to pass through. Since both dimers share a high sequence homology, their folding is identical. The dimers are linked by a disulfide bond between the central, five-stranded beta sheet at the two residues. This interaction is most likely stabilized by the alpha helix of one monomer and the beta sheet of another.  

III. ecTBR2- Structure

ecTBR2 is composed primarily of along with a single 3-10 . Each of the nine beta strands lays on a flat plain to form a waffle shape. Beta strands 1, 2, 4, 3, 5, and 6 form one large beta sheet which is antiparallel to the second sheet of strands 1 prime, 1 double prine, and 7. The most essential of the beta strands is strand four which is where the ligand, TGF-B3, binds.

Among the ecTBR2 superfamily, there are four highly conserved disulfide bonds between of beta strands 1 and 3 as well as of beta strands 2 and 4, of beta strands 5 and 6, and of beta strands 6 and 7. In addition, disulfide bonds between of beta prime and beta double prime which occur exclusively in ecTBR2.

IV. TGF-B3 and ecTBR2 Binding

The ligand binds to its receptor, with high affinity as it has a dissociation constant of 500pM. When TGF-B3 binds ecTBR2, it undergoes a structural conformation. It is thought that this conformation exposes the ecTBR1 binding site and allows ecTBR1 to be recruited after which it is subsequently phosphorylated by ecTBR2. Once this occurs, ecTBR1 is able to propagate cell signals further to its intracellular targets. In this way, the binding of TGF-B3 to ecTBR2 is a critical step in the phosphorylation of ecTBR1. Mullerian inhibiting substance and activin, TGF-B superfamily members, also utilize this sequential mode of binding

The structure of ecTBR2 is composed mostly of beta sheets, the most essential of which is B-strand 4. ecTBR2 uses the amino acids Ile 50, Thr 51 , and Ile 53 of B-strand 4 along with Leu 27 and Phe 30 of B-strand 1 to form a convex . This bridge is linked to TGF-B3 at a formed by Trp 32 of fingers 1 and 2 and Tyr 90, Tyr 91, and Val 92 of fingers 3 and 4.

V. Acknowledgements

A special thanks to Dr. Powell for imparting us with Biology knowledge, to previous Bio 263 classes for teaching us how to code, and to the 2013 Bio 263 class for editing our projects.

VI. References

Boesen, C., Radaev S., Motyka, S., Patamawenu, A., and P. Sun. (2002) The 1.1 Angstrom Crystal Structure of Human TGF-B Type II Receptor Ligand Binding Domain. Structure.10: 913-919.

Cox, D. (1995) Transforming Growth Factor- Beta 3. Cell Biology International, 19(5): 357-371.

Hart, J., Deep Shashank, Taylor A., Shu Z., Hinck C., Hinck A. (2002) Crystal structure of the human TBR2- ectodomain-TGF-B3 complex. Nature Structural Biology, 9(3): 203-208.