Structural highlights
Function
[1433G_HUMAN] Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner.[1]
Publication Abstract from PubMed
Tyrosine hydroxylase (TH) catalyzes the rate-limiting step in the synthesis of catecholamine neurotransmitters, and a reduction in TH activity is associated with several neurological diseases. Human TH is regulated, among other mechanisms, by Ser19-phosphorylation-dependent interaction with 14-3-3 proteins. The N-terminal sequence (residues 1-43), which corresponds to an extension to the TH regulatory domain, also interacts with negatively charged membranes. By using X-ray crystallography together with molecular dynamics simulations and structural bioinformatics analysis, we have probed the conformations of the Ser19-phosphorylated N-terminal peptide [THp-(1-43)] bound to 14-3-3gamma, free in solution and bound to a phospholipid bilayer, and of the unphosphorylated peptide TH-(1-43) both free and bilayer bound. As seen in the crystal structure of THp-(1-43) complexed with 14-3-3gamma, the region surrounding pSer19 adopts an extended conformation in the bound state, whereas THp-(1-43) adopts a bent conformation when free in solution, with higher content of secondary structure and higher number of internal hydrogen bonds. TH-(1-43) in solution presents the highest mobility and least defined structure of all forms studied, and it shows an energetically more favorable interaction with membranes relative to THp-(1-43). Cationic residues, notably Arg15 and Arg16, which are the recognition sites of the kinases phosphorylating at Ser19, are also contributing to the interaction with the membrane. Our results reveal the structural flexibility of this region of TH, in accordance with the functional versatility and conformational adaptation to different partners. Furthermore, this structural information has potential relevance for the development of therapeutics for neurodegenerative disorders, through modulation of TH-partner interactions.
The N-Terminal Sequence of Tyrosine Hydroxylase Is a Conformationally Versatile Motif That Binds 14-3-3 Proteins and Membranes.,Skjevik AA, Mileni M, Baumann A, Halskau O, Teigen K, Stevens RC, Martinez A J Mol Biol. 2013 Sep 17. pii: S0022-2836(13)00583-4. doi:, 10.1016/j.jmb.2013.09.012. PMID:24055376[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Jin Y, Dai MS, Lu SZ, Xu Y, Luo Z, Zhao Y, Lu H. 14-3-3gamma binds to MDMX that is phosphorylated by UV-activated Chk1, resulting in p53 activation. EMBO J. 2006 Mar 22;25(6):1207-18. Epub 2006 Mar 2. PMID:16511572 doi:10.1038/sj.emboj.7601010
- ↑ Skjevik AA, Mileni M, Baumann A, Halskau O, Teigen K, Stevens RC, Martinez A. The N-Terminal Sequence of Tyrosine Hydroxylase Is a Conformationally Versatile Motif That Binds 14-3-3 Proteins and Membranes. J Mol Biol. 2013 Sep 17. pii: S0022-2836(13)00583-4. doi:, 10.1016/j.jmb.2013.09.012. PMID:24055376 doi:http://dx.doi.org/10.1016/j.jmb.2013.09.012
