Tribbles homolog 1 is a protein kinase that in humans is encoded by the TRIB1gene.[1][2][3]Orthologs of this protein pseudokinase (pseudoenzyme) can be found almost ubiquitously throughout the animal kingdom.[4] It exerts its biological functions through binding to signalling proteins of the MAPKK level of the MAPK pathway, therefore eliciting a regulatory role in the function of this pathway which mediates proliferation, apoptosis and differentiation in cells. Tribbles-1 is encoded by the trib1 gene, which in humans can be found on chromosome 8 at position 24.13 on the longest arm (q). Recent crystal structures show that Tribbles 1 has an unusual 3D structure, containing a 'broken' C-helix region, a binding site for ubiquitinated substrates such as C/EBPalpha and a key regulatory C-tail region.[5] Like TRIB2 and TRIB3, TRIB1 has recently been considered as a potential allosteric drug target [6]
Tribbles-1 is one of three members of the Tribbles subfamily, which is a part of the CAMK Ser/Thr protein kinase family, of the protein kinase superfamily. The Tribbles subfamily is one of the pseudokinases, meaning that while expressing putative kinase regions in its structure, it is non-catalytic. The Tribbles subfamily lacks a functional ATP binding pocket, and therefore cannot phosphorylate its substrates; instead, Tribbles proteins function as scaffold proteins, which bind their substrates to localize them to or from their function [4]
Expression of Tribbles-1 is highly variable, constantly changing with respect to time and cell-type,[7] which suggests a large amount of regulation that exists in the cell. The protein's primary structure contains a PEST region, indicative of proteins that are highly susceptible to degradation in the cell; Tribbles-1 plays a role in regulating its own expression by binding to its substrate, which not only produces its function on the MAPK pathway, but also works to protect it from degradation whilst binding. This, in part, creates a positive feedback loop in the function of Tribbles-1, as the function of Tribbles-1 directly aids in the increase of the amount of it. As positive feedback loops are often seen throughout biology in circumstances that require the alleviation of an external stimulus, the positive feedback loop exhibited by Tribbles-1 suggests that it plays a functional role in cell response.
Clinical significance
Tribbles-1 is an inflammatory regulator.
Tribbles-1 is associated with Acute Myeloid Leukemia (AML).
Tribbles-1 has been implicated in atherosclerosis.
References
↑Wilkin F; Suarez-Huerta N; Robaye B; Peetermans J; Libert F; Dumont JE; Maenhaut C (Nov 1997). "Characterization of a phosphoprotein whose mRNA is regulated by the mitogenic pathways in dog thyroid cells". Eur J Biochem. 248 (3): 660–68. doi:10.1111/j.1432-1033.1997.t01-1-00660.x. PMID9342215.
↑Hegedus Z, Czibula A, Kiss-Toth E (Aug 2006). "Tribbles: novel regulators of cell function; evolutionary aspects". Cell Mol Life Sci. 63 (14): 1632–41. doi:10.1007/s00018-006-6007-9. PMID16715410.
↑Eyers PA, Keeshan K, Kannan N (2015). "Molecular Mechanism of CCAAT-Enhancer Binding Protein Recruitment by the TRIB1 Pseudokinase". Structure. 23 (11): 2111–2121. doi:10.1016/j.str.2015.08.017. PMID26455797.
↑Foulkes DM, Byrne DP, Eyers PA (2015). "Tribbles pseudokinases: novel targets for chemical biology and drug discovery?". Biochemical Society Transactions. 43 (5): 1095–1103. doi:10.1042/BST20150109. PMID26517930.
↑Sung HY, Francis SE, Crossman DC, Kiss-Toth E (Apr 2006). "Regulation of expression and signalling modulator function of mammalian tribbles is cell-type specific". Immunology Letters. 104 (1–2): 171–177. doi:10.1016/j.imlet.2005.11.010. PMID16364454.
Further reading
Tang K, Finley RL, Nie D, Honn KV (2000). "Identification of 12-lipoxygenase interaction with cellular proteins by yeast two-hybrid screening". Biochemistry. 39 (12): 3185–91. doi:10.1021/bi992664v. PMID10727209.
Wu M, Xu LG, Zhai Z, Shu HB (2003). "SINK is a p65-interacting negative regulator of NF-kappaB-dependent transcription". J. Biol. Chem. 278 (29): 27072–9. doi:10.1074/jbc.M209814200. PMID12736262.
Kiss-Toth E, Bagstaff SM, Sung HY, et al. (2004). "Human tribbles, a protein family controlling mitogen-activated protein kinase cascades". J. Biol. Chem. 279 (41): 42703–8. doi:10.1074/jbc.M407732200. PMID15299019.
Xu C, Zhang J, Huang X, et al. (2006). "Solution structure of human peptidyl prolyl isomerase-like protein 1 and insights into its interaction with SKIP". J. Biol. Chem. 281 (23): 15900–8. doi:10.1074/jbc.M511155200. PMID16595688.
