| Structural highlights
Function
[DDIT4_HUMAN] Regulates cell growth, proliferation and survival via inhibition of the activity of the mammalian target of rapamycin complex 1 (mTORC1). Inhibition of mTORC1 is mediated by a pathway that involves DDIT4/REDD1, AKT1, the TSC1-TSC2 complex and the GTPase RHEB. Plays an important role in responses to cellular energy levels and cellular stress, including responses to hypoxia and DNA damage. Regulates p53/TP53-mediated apoptosis in response to DNA damage via its effect on mTORC1 activity. Its role in the response to hypoxia depends on the cell type; it mediates mTORC1 inhibition in fibroblasts and thymocytes, but not in hepatocytes (By similarity). Required for mTORC1-mediated defense against viral protein synthesis and virus replication (By similarity). Inhibits neuronal differentiation and neurite outgrowth mediated by NGF via its effect on mTORC1 activity. Required for normal neuron migration during embryonic brain development. Plays a role in neuronal cell death.[1] [2] [3] [4] [5] [6] [7] [8]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
REDD1 is a conserved stress-response protein that regulates mTORC1, a critical regulator of cell growth and proliferation that is implicated in cancer. REDD1 is induced by hypoxia, and REDD1 overexpression is sufficient to inhibit mTORC1. mTORC1 is regulated by the small GTPase Rheb, which in turn is regulated by the GTPase-activating protein complex, TSC1/TSC2. REDD1 induced-mTORC1 inhibition requires the TSC1/TSC2 complex, and REDD1 has been proposed to act by directly binding to and sequestering 14-3-3 proteins away from TSC2 leading to TSC2-depedent inhibition of mTORC1. Structure/function analyses have led us to identify two segments in REDD1 that are essential for function, which act in an interdependent manner. We have determined a crystal structure of REDD1 at 2.0 A resolution, which shows that these two segments fold together to form an intact domain with a novel fold. This domain is characterized by an alpha/beta sandwich consisting of two antiparallel alpha-helices and a mixed beta-sheet encompassing an uncommon psi-loop motif. Structure-based docking and functional analyses suggest that REDD1 does not directly bind to 14-3-3 proteins. Sequence conservation mapping to the surface of the structure and mutagenesis studies demarcated a hotspot likely to interact with effector proteins that is essential for REDD1-mediated mTORC1 inhibition.
Structural Analysis and Functional Implications of the Negative mTORC1 Regulator REDD1 (,).,Vega-Rubin-de-Celis S, Abdallah Z, Kinch L, Grishin NV, Brugarolas J, Zhang X Biochemistry. 2010 Mar 2. PMID:20166753[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW, Kaelin WG Jr. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev. 2004 Dec 1;18(23):2893-904. Epub 2004 Nov 15. PMID:15545625 doi:10.1101/gad.1256804
- ↑ Corradetti MN, Inoki K, Guan KL. The stress-inducted proteins RTP801 and RTP801L are negative regulators of the mammalian target of rapamycin pathway. J Biol Chem. 2005 Mar 18;280(11):9769-72. Epub 2005 Jan 4. PMID:15632201 doi:http://dx.doi.org/10.1074/jbc.C400557200
- ↑ Sofer A, Lei K, Johannessen CM, Ellisen LW. Regulation of mTOR and cell growth in response to energy stress by REDD1. Mol Cell Biol. 2005 Jul;25(14):5834-45. PMID:15988001 doi:http://dx.doi.org/10.1128/MCB.25.14.5834-5845.2005
- ↑ Malagelada C, Ryu EJ, Biswas SC, Jackson-Lewis V, Greene LA. RTP801 is elevated in Parkinson brain substantia nigral neurons and mediates death in cellular models of Parkinson's disease by a mechanism involving mammalian target of rapamycin inactivation. J Neurosci. 2006 Sep 27;26(39):9996-10005. PMID:17005863 doi:http://dx.doi.org/10.1523/JNEUROSCI.3292-06.2006
- ↑ Gery S, Park DJ, Vuong PT, Virk RK, Muller CI, Hofmann WK, Koeffler HP. RTP801 is a novel retinoic acid-responsive gene associated with myeloid differentiation. Exp Hematol. 2007 Apr;35(4):572-8. PMID:17379067 doi:http://dx.doi.org/10.1016/j.exphem.2007.01.049
- ↑ Katiyar S, Liu E, Knutzen CA, Lang ES, Lombardo CR, Sankar S, Toth JI, Petroski MD, Ronai Z, Chiang GG. REDD1, an inhibitor of mTOR signalling, is regulated by the CUL4A-DDB1 ubiquitin ligase. EMBO Rep. 2009 Aug;10(8):866-72. doi: 10.1038/embor.2009.93. Epub 2009 Jun 26. PMID:19557001 doi:http://dx.doi.org/10.1038/embor.2009.93
- ↑ Jin HO, Seo SK, Kim YS, Woo SH, Lee KH, Yi JY, Lee SJ, Choe TB, Lee JH, An S, Hong SI, Park IC. TXNIP potentiates Redd1-induced mTOR suppression through stabilization of Redd1. Oncogene. 2011 Sep 1;30(35):3792-801. doi: 10.1038/onc.2011.102. Epub 2011 Apr 4. PMID:21460850 doi:10.1038/onc.2011.102
- ↑ Vega-Rubin-de-Celis S, Abdallah Z, Kinch L, Grishin NV, Brugarolas J, Zhang X. Structural Analysis and Functional Implications of the Negative mTORC1 Regulator REDD1 (,). Biochemistry. 2010 Mar 2. PMID:20166753 doi:10.1021/bi902135e
- ↑ Vega-Rubin-de-Celis S, Abdallah Z, Kinch L, Grishin NV, Brugarolas J, Zhang X. Structural Analysis and Functional Implications of the Negative mTORC1 Regulator REDD1 (,). Biochemistry. 2010 Mar 2. PMID:20166753 doi:10.1021/bi902135e
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