Calcium signal generation mechanisms
signaling systems translate external signals such as
hormones, growth factors or neurotransmitters into
intracellular second messengers. These messengers can
serve a number of functions, by turning on or off
specific pathways. Two important second messengers are
Ca2+ and inositol 1,4,5-trisphosphate (IP3). The
concentration of Ca2+ in the cell is tightly regulated by
various ion transporters. To understand how the Ca2+
signal is created, we need to investigate the mechanism
of Ca2+ transportation in the cell. We are currently
studying two major Ca2+ transporters, IP3 receptors and
sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA). The
former is implicated in neurological disorders such as
cerebellar ataxia and epileptic seizures, and the latter
is implicated in heart diseases. While IP3 receptors act
as a Ca2+ release channel on internal stores within the
endoplasmic reticulum (ER), SERCA is a Ca2+ pump which
translocates cytoplasmic Ca2+ into the internal stores.
Our current work focuses on the structural determination
of the cytoplasmic ligand binding portions of IP3
receptors and SERCA by X-ray crystallography or NMR
Alattia, J.R., Mal, T.K., Chan, J., Talarico, S., Tong,
F.K., Tong, K.I., Yoshikawa, F., Furuichi, T., Iwai, M.,
Michikawa, T., Mikoshiba, K., and Ikura, M. Structure of
the inositol 1,4,5-trisphosphate receptor binding core in
complex with its ligand. Nature. Dec 12
M., Mal, T.K., Kainosho, M., MacLennan, D.H., and Ikura,
M. Characterization of the ATP-binding domain of the
sarco(endo)plasmic reticulum Ca(2+)-ATPase: probing
nucleotide binding by multidimensional NMR.
Biochemistry. Jan 29;41(4):1156-64.
Abu-Abed, M., Millet, O., MacLennan, D.H., and Ikura, M. Probing nucleotide-binding effects on backbone dynamics and folding of the nucleotide-binding domain of the sarcoplasmic/endoplasmic-reticulum Ca2+-ATPase. Biochem J. Apr 15;379(Pt 2):235-42.
Calcium signal sensing mechanismsThe calcium ion serves as a second messenger in eukaryotes. Calmodulin is a ubiquitous calcium sensor which transmits the calcium signal into a wide variety of cellular processes including muscle contraction, neural signal transduction and cell differentiation. We have determined the solution structure of calcium-free calmodulin (1DMO) and calcium-bound calmodulin complexed with antagonist W-7 (1MUX). In 1999, we determined the solution structure of calmodulin in complex with a Ca2+/Calmodulin-dependent kinase kinase peptide (1CKK) , which revealed a novel mechanism for calmodulin-target recognition (Osawa et al., 1999). In 2001, the 1.9Å crystal structure of calmodulin bound to C. elegan calmodulin kinase kinase was determined in our laboratory (1IQ5), (Kurakawa et al., 2001). Our goal is to understand how calmodulin transmits the calcium signal to its target proteins and what structural features are critical for its multi-functionality.
Kurokawa, H., Osawa, M., Kurihara, H., Katayama, N., Tokumitsu, H., Swindells, M., Kainoshi, M., and Ikura, M. 2001. Target-induced conformational adaptation of calmodulin revealed by the crystal structure of a complex with nematode Ca2+/calmodulin-dependent kinase kinase peptide, Sep 7; 312 (1): 59-68.
Osawa, M., Tokumitsu, H., Swindells, M.B., Kurihara, H., Orita, M., Shibanuma, T., Furuya, T., and Ikura, M. (1999) A Novel Target Recognition by Calmodulin Revealed by its Solution Structure in Complex with a Peptide Derived from Ca2+/Calmodulin Dependent Protein Kinase Kinase. Nat. Struct. Biol. 6, 819-824.
Ikura, M. (1996) Calcium Binding and Conformational Response by EF-hand Proteins. Trends in Biochem. Sci. 21, 14-17.
Ikura, M. (1996) "Calmodulin" Encyclopedia of NMR. John Wiley & Sons, Ltd. 1100-1106.
Zhang, M., Tanaka, T. and Ikura, M. (1995) Solution Structure of Apocalmodulin: Conformational Transition Induced by Calcium Binding. Nature Struct. Biol. 2,758-767.
Crivici, A. and Ikura, M. (1995) Molecular and Structural Basis of Target Recognition by Calmodulin. Annual Review of Biophys. and Biomol. Struct. 24, 85-116.
Calcium Myristoyl SwitchesRecoverin is a calcium sensor in vision. This myristoylated, EF-hand protein acts as a calcium myristoyl switch in the retina. We have solved the solution structures of calcium-free recoverin (1IKU) and calcium-bound recoverin (1JSA) in collaboration with Dr. L. Stryer. We would like to understand how recoverin translocates in the retina's outer segment membrane in a calcium dependent manner and regulates the activity of rhodopsin kinase.
Ames, J.B., Ishima, R., Tanaka, T., Gordon, J.I., Stryer, L. and Ikura, M. (1997) Molecular Mechanics of Calcium-myristoyl Switches. Nature 389, 198-202.
Tanaka, T., Ames, J.B., Harvey, T.S., Stryer, L. and Ikura, M. (1995) Sequestration of the Membrane-targetting Myristoyl Group of Recoverin in the Calcium-free State. Nature 376, 444-448.