The overall objective of the proposed study is to understand the structural basis for molecular recognition and assembly between TGF-beta family ligands and cell surface receptors. The TGF-beta ligands exert a wide range of biological functions. Two types of receptors involved in the signaling cascade, each with a single transmembrane helix and a cytoplasmic Ser/Thr kinase domain, form a large protein complex with the ligand to initiate the signaling process. Our specific goal is to have a structural understanding on how the binding of ligands to the extracellular domain of the first receptor, and its subsequent complex with the other receptor transduces the message to the downstream components of the signaling pathway. Bone morphogenetic proteins (BMP) is a subfamily of TGF-beta ligand superfamily. We will focus on Activin/BMP signaling system to address these questions. In addition, we will study the Activin/BMP interaction with its antagonist Noggin. We will study structures of ligand-binding domain of inhibin receptor. In this study, our primary focus is two-fold: 1) to decode fundamental structural determinants specific and common among those ligands, and 2) to understand conformational changes in the ligand induced upon complex formation with respect to the biological signaling outputs. Based on stoichiometric ratios and binding affinity of different ligand/receptor complexes, we will establish the thermodynamic and kinetic rates of the processes. Additionally, we will determine structures of BMP variants in complex with Noggin. I believe results from these studies will provide a firm basis to understand structural basis for molecular recognition and receptor assembly, from which we can facilitate the design of effective therapeutic means to be used in modulating various hormone-related and neurological diseases.
| Muenster, Uwe; Korupolu, Radhika; Rastogi, Ratindra et al. (2011) Antagonism of activin by activin chimeras. Vitam Horm 85:105-28 |
| Kim, Meejung; Choe, Senyon (2011) BMPs and their clinical potentials. BMB Rep 44:619-34 |
| Looyenga, Brendan D; Wiater, Ezra; Vale, Wylie et al. (2010) Inhibin-A antagonizes TGFbeta2 signaling by down-regulating cell surface expression of the TGFbeta coreceptor betaglycan. Mol Endocrinol 24:608-20 |
| Valera, Elvira; Isaacs, Michael J; Kawakami, Yasuhiko et al. (2010) BMP-2/6 heterodimer is more effective than BMP-2 or BMP-6 homodimers as inductor of differentiation of human embryonic stem cells. PLoS One 5:e11167 |
| Isaacs, Michael J; Kawakami, Yasuhiko; Allendorph, George P et al. (2010) Bone morphogenetic protein-2 and -6 heterodimer illustrates the nature of ligand-receptor assembly. Mol Endocrinol 24:1469-77 |
| Hassold, Terry; Hunt, Patricia (2009) Maternal age and chromosomally abnormal pregnancies: what we know and what we wish we knew. Curr Opin Pediatr 21:703-8 |
| Wiater, Ezra; Lewis, Kathy A; Donaldson, Cynthia et al. (2009) Endogenous betaglycan is essential for high-potency inhibin antagonism in gonadotropes. Mol Endocrinol 23:1033-42 |
| Cheng, Edith Y; Hunt, Patricia A; Naluai-Cecchini, Theresa A et al. (2009) Meiotic recombination in human oocytes. PLoS Genet 5:e1000661 |
| Ciarmela, Pasquapina; Wiater, Ezra; Smith, Sean M et al. (2009) Presence, actions, and regulation of myostatin in rat uterus and myometrial cells. Endocrinology 150:906-14 |
| Blount, Amy L; Vaughan, Joan M; Vale, Wylie W et al. (2008) A Smad-binding element in intron 1 participates in activin-dependent regulation of the follistatin gene. J Biol Chem 283:7016-26 |
Showing the most recent 10 out of 258 publications
