studies two enigmatic orphan nuclear receptors, LRH-1 and SF-1, and their physiological regulatory partner, orphan nuclear receptor Dax-1. Dax-1 is indispensable in embryogenesis and vital for maintenance of pluripotent state of ES cells. Because of its critical role in human development and physiology, Dax-1 is the central target of current studies. We recently expanded the study of regulatory mechanisms by Dax-1 to Nanog, a key transcriptional regulator and marker of the pluripotent state of embryonic stem (ES) cells.
In collaboration with Dr. Holly Ingraham (UCSF), we have determined the crystal structures of the ligand binding domains (LBDs) of LRH-1 and SF-1 to 2.4 Å and 1.2 Å resolution, respectively. These structural studies suggested a model for constitutive transcriptional activity of these receptors and revealed phosphatidyl inositols as potential functional ligands for LRH-1 and SF-1. We have also determined the first structure of Dax-1 in a trimeric complex with its physiological target, LRH-1. This unusual trimeric assembly might explain how Dax-1 regulates multiple partners in reproductive tissues and embryonic stem cells.
Sablin EP, Blind RD, Krylova IN, Ingraham JG, Cai F, Williams JD, Fletterick RJ, and HA Ingraham (2009) Structure of SF-1 bound by different phospholipids: evidence for regulatory ligands. Mol Endocrinol. 23, 25-34.
Sablin EP, Woods A, Krylova IN, Hwang P, Ingraham HA, and R.J. Fletterick (2008) The structure of corepressor Dax-1 bound to its target nuclear receptor LRH-1. Proc Natl Acad Sci USA 105, 18390-5.
Krylova IN., Sablin EP, Moore J, Xu RX, Waitt GM, McKay JA, Juzumiene D, Bynum JM, Madause K, Montana V, Lebedeva L, Suzawa M, Williams JD, Williams SP, Guy RK, Thornton JW, Fletterick RJ, Willson TM and HA Ingraham (2005) Structural analyses reveal phosphatidyl inositols as ligands for the NR5 orphan receptors SF-1 and LRH-1. Cell 120, 343-355.
Sablin EP, Krylova IN, Fletterick RJ, and HA Ingraham (2003) Structural basis for ligand-independent activation of the orphan nuclear receptor LRH-1. Mol Cell 11, 1575-85.
works on the regulation of the kinesin motor. Her two projects on kinesin regulation
are: 1) crystallization of the kinesin-like calmodulin binding protein (KCBP) in the complex with its regulator, either calmodulin or a novel single EF-hand, plant specific protein KIC, and 2) crystallization of the complex of the kinesin CENP-E and its cargo binding protein – protein kinase BUBR1 which is involved in mitotic checkpoint. She also works on defining ligands in binding to androgen receptor by X-ray crystallography.
Maia is also studying the skeletal muscle ternary complex in both relaxed and calcium-activated forms. The goal of this project is to find a drug capable of increasing the muscle strength and Ca2+-sensitivity of muscle contractions.
Maia previously determined the structure of troponin with and without calcium.
Vinogradova MV, Malanina GG, Reddy AS, Fletterick RJ. (2009) Structure of the complex of a mitotic kinesin with its calcium binding regulator. Proc Natl Acad Sci U S A. May 19; 106(20):8175-9.
Vinogradova M, Malanina G, Reddy V, Reddy A and RJ Fletterick. (2008) Structural dynamics of the microtubule binding and regulatory elements in the kinesin-like calmodulin binding protein. J Structural Biology 2008 J Struct Biol. 2008 Jul;163(1):76-83.
Vinogradova MV, Stone DB, Malanina GG, Mendelson RA, Fletterick RJ. (2007) Ca ion and the troponin switch. Adv Exp Med Biol.592:47-57. Review.