5f74
From Proteopedia
Crystal structure of ChREBP:14-3-3 complex bound with AMP
Structural highlights
Function[1433B_MOUSE] 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. Negative regulator of osteogenesis. Blocks the nuclear translocation of the phosphorylated form (by AKT1) of SRPK2 and antagonizes its stimulatory effect on cyclin D1 expression resulting in blockage of neuronal apoptosis elicited by SRPK2 (By similarity). [MLXPL_RAT] Transcriptional repressor. Binds to the canonical and non-canonical E box sequences 5'-CACGTG-3' (By similarity). Publication Abstract from PubMedThe carbohydrate responsive element-binding protein (ChREBP) is a glucose-responsive transcription factor that plays the essential role in converting excess carbohydrate to fat storage in the liver. In response to glucose level, ChREBP is regulated by nuclear/cytosol trafficking via interaction with either 14-3-3 proteins, CRM-1 (Exportin-1 or XPO-1), or importins. Nuclear localization of ChREBP was rapidly inhibited when incubated in branched-chain alpha-ketoacids, saturated and unsaturated fatty acids or AICAR. Here, we discovered that protein-free extracts of high fat-fed livers contained, in addition to ketone bodies, a new metabolite, identified as AMP, which specifically activates the interaction between ChREBP and 14-3-3. The crystal structure showed that AMP binds directly to the N-terminus of ChREBP-alpha2 helix. Our results suggest that AMP inhibits the nuclear localization of ChREBP through an allosteric activation of ChREBP/14-3-3 interactions, and not by activation of AMPK. AMP and ketone bodies together can therefore inhibit lipogenesis by restricting localization of ChREBP to the cytoplasm during periods of ketosis. Metabolite Regulation of Nuclear Localization of Carbohydrate Response Element-binding Protein (ChREBP). Role of AMP as an Allosteric Inhibitor.,Sato S, Jung H, Nakagawa T, Pawlosky R, Takeshima T, Lee WR, Sakiyama H, Laxman S, Wynn RM, Tu B, MacMillan JB, De Brabander JK, Veech RL, Uyeda K J Biol Chem. 2016 Mar 16. pii: jbc.M115.708982. PMID:26984404[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Jung, H | Uyeda, K | 14-3-3 | Allosteric | Amp | Chrebp | Transcription
