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|Functional site class:||CtBP ligand motif|
|Functional site description:||The PxDLS motif is present in a number of nuclear proteins, including certain transcription factors and HDACs, that recruit CtBP (C-terminal binding protein) into nuclear complexes. CtBP has a generally repressive effect on transcription and must be removed to active CtBP regulated genes.|
|Description:||The PxDLS motif pattern is based on the conservation of reported sequence instances together with the structure of the CtBP domain in complex with a PxDLS peptide (1HL3 ). Beta-augmentation at the sheet edge places the peptide sidechains in specific places on the CtBP surface. Pro at position 1 makes an H-bond to strand edge backbone and fits in a hydrophobic pocket that will not accommodate other residues (Gly with no side chain may be the least disruptive). Position 2 contributes to beta augmentation so that the semiconserved sidechain is placed in a shallow hydrophobic pocket which also allows Glu due to proximity of surface positive charge. Position 3 is most often Asp, probably due to facourable charged residue proximity but is surface accessible and accepts some changes. Position 4 contributes to beta augmentation so that the sidechain enters a deep hydrophobic groove that fits to Leu and would probably allow Met but reject most other residues. Position 5 has a Ser-Thr preference but appears to accept R (as in HDACs) and some other mostly small residues. Following the core peptide there are clear preferences for Lys or Arg but these are not a strict requirement. However the conserved GLDLSKK motif in Hic1 is reported to bind CtBP but lacks Pro: Therefore for Gly at position 1 which must weaken the interaction, the motif in ELM requires C-terminal positive charge compensation.|
|Present in taxons:||Metazoa|
The CtBP (C-terminal binding protein) protein was first identified by Boyd at al. 1993 8440238, where a short region in adenovirus E1A was found essential in its interaction with CtBP. Deletion of this region in E1A resulted in increased transcriptional activity, suggesting that CtBP might be a co-repressor for E1A. Several eukaryotic proteins such as Hairy, Knirps, Ikaros, Polycomb and several zinc finger proteins interact with CtBP through a short motif with the consensus PxDLS (see review 11864595). CtBP is structurally related to dehydrogenases and is indeed a NAD-dependent dehydrogenase (12419229). CtBP interacts with the PxDLS motif through its dehydrogenase domain, in a NAD+ dependent manner. CtBP proteins dimerise (vertebrate CtBP1 and CtBP2 can homo or heterodimerise) and can simultaneously interact with two PxDLS containing proteins, e.g. with a DNA binding protein and a repressor. Binding to NAD+/NADPH aids dimerisation and therefore CtBP is sensitive to nutritional status (21281737). A second role for CtBP in Golgi membrane fission may not involve PxDLS motifs (16483777).
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