The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Accession:
Functional site class:
CtBP ligand motifs
Functional site description:
The C-terminal binding proteins (CtBP) are involved in multiple processes, including gene regulation, where they function as transcriptional corepressors by recruiting a repressor complex. CtBP itself is recruited to target genes by transcription factors belonging to diverse families through motif mediated interactions: the PxDLS motif that binds to a cleft on the substrate binding domain of CtBP, and the RRT motif that binds to a distinct surface cleft in the nucleotide binding domain of CtBP. These two binding sites are on opposite sides of a CtBP molecule, however in a CtBP homodimer the PxDLS binding site of one subunit is located adjacent to the RRT binding site of the other subunit, theoretically allowing binding of a ligand containing both motifs across the CtBP dimer.
ELMs with same func. site: LIG_CtBP_PxDLS_1  LIG_CtBP_RRT_2 
ELM 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 semi-conserved 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 favourable 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.
Pattern: (P[LVIPME][DENS][LM][VASTRG])|(G[LVIPME][DENS][LM][VASTRG]((K)|(.[KR])))
Pattern Probability: 0.0001173
Present in taxon: Metazoa
Interaction Domain:
2-Hacid_dh (PF00389) D-isomer specific 2-hydroxyacid dehydrogenase, catalytic domain (Stochiometry: 1 : 1)
o See 32 Instances for LIG_CtBP_PxDLS_1
o Abstract
The CtBP (C-terminal binding protein) protein is structurally related to dehydrogenases and is indeed a NAD-dependent dehydrogenase (Kumar,2002). It was originally discovered as a protein associating with adenovirus E1A. Deletion of a short region in E1A that was found to be essential for the interaction with CtBP resulted in increased transcriptional activity, suggesting that CtBP might be a co-repressor for E1A (Boyd,1993). 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 (Chinnadurai,2002). 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 (Jack,2011). A second role for CtBP in Golgi membrane fission may not involve PxDLS motifs (Corda,2006). Interestingly, several zinc finger proteins such as RIZ and ZNF217 were found to contain a second motif mediating binding to CtBP, in addition to the typical PxDLS motif. This second motif, known as the RRT motif, binds to a separate surface on CtBP, distinct from the PxDLS binding cleft (Quinlan,2006).

o 8 selected references:

o 8 GO-Terms:

o 32 Instances for LIG_CtBP_PxDLS_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
P03254 Early E1A 32
E1A_ADE02
279 283 EDLLNESGQPLDLSCKRPRP TP 5 Human adenovirus 2
1 
Q9UQL6 HDAC5
HDAC5_HUMAN
56 60 GGGGSPSPVELRGALVGSVD TP 1 Homo sapiens (Human)
Q14526 HIC1
HIC1_HUMAN
241 246 RRCSPLCGLDLSKKSPPGSA TP 1 Homo sapiens (Human)
O60315 ZEB2
ZEB2_HUMAN
859 863 SSENSDEPLNLTFIKKEFSN TP 1 Homo sapiens (Human)
O60315 ZEB2
ZEB2_HUMAN
815 819 SEELQAEPLDLSLPKQMKEP TP 1 Homo sapiens (Human)
O60315 ZEB2
ZEB2_HUMAN
785 789 SRSNTPSPLNLSSTSSKNSH TP 1 Homo sapiens (Human)
P70062 tcf7l1-a
T7L1A_XENLA
545 549 LQALPLLQAQPLSLVTKSSD TP 1 Xenopus laevis (African clawed frog)
P70062 tcf7l1-a
T7L1A_XENLA
469 473 THSEQAQPLSLTTKPEARAQ TP 1 Xenopus laevis (African clawed frog)
Q9UHF7 TRPS1
TRPS1_HUMAN
1163 1167 VGSDNDIPLDLAIKHSRPGP TP 1 Homo sapiens (Human)
Q9H2S9 IKZF4
IKZF4_HUMAN
425 429 SREAGEGPEDLADGGPLLYR TP 1 Homo sapiens (Human)
O00257 CBX4
CBX4_HUMAN
472 476 LDSDLDEPIDLRCVKTRSEA TP 1 Homo sapiens (Human)
Q91647 cbx4
Q91647_XENLA
455 459 LDSDLDEPIDLRCVKSRCDS TP 1 Xenopus laevis (African clawed frog)
Q8IX07 ZFPM1
FOG1_HUMAN
794 798 PGPAADGPIDLSKKPRRPLP TP 1 Homo sapiens (Human)
Q96JN0 LCOR
LCOR_HUMAN
64 68 LMADQDSPLDLTVRKSQSEP TP 1 Homo sapiens (Human)
Q15583 TGIF1
TGIF1_HUMAN
153 157 DEDSMDIPLDLSSSAGSGKR TP 1 Homo sapiens (Human)
P35712 SOX6
SOX6_HUMAN
424 428 KDEAAAQPLNLSSRPKTAEP TP 1 Homo sapiens (Human)
P17789 ttk
TTKB_DROME
593 597 SGASTPPPPDLSGQNSNQSL TP 1 Drosophila melanogaster (Fruit fly)
P56524 HDAC4
HDAC4_HUMAN
48 52 QVAPSAVPMDLRLDHQFSLP TP 1 Homo sapiens (Human)
Q8C2B3 Hdac7
HDAC7_MOUSE
22 26 TPGSQPQPMDLRVGQRPTVE TP 1 Mus musculus (House mouse)
Q99N13 Hdac9
HDAC9_MOUSE
23 27 MGLEPISPLDLRTDLRMMMP TP 1 Mus musculus (House mouse)
P28166 zfh1
ZFH1_DROME
786 790 SLTREDQPLDLSVKRDPLTP TP 1 Drosophila melanogaster (Fruit fly)
P14003 h
HAIR_DROME
318 322 RVPMEQQPLSLVIKKQIKEE TP 1 Drosophila melanogaster (Fruit fly)
P41970 ELK3
ELK3_HUMAN
273 277 HDSDSLEPLNLSSGSKTKSP TP 1 Homo sapiens (Human)
Q13422 IKZF1
IKZF1_HUMAN
34 38 GDEPMPIPEDLSTTSGGQQS TP 1 Homo sapiens (Human)
Q8WW38 ZFPM2
FOG2_HUMAN
829 833 SCLEMDVPIDLSKKCLSQSE TP 1 Homo sapiens (Human)
P48552 NRIP1
NRIP1_HUMAN
440 444 SSYSNCVPIDLSCKHRTEKS TP 1 Homo sapiens (Human)
P10734 kni
KNIR_DROME
331 335 TVSAQEGPMDLSMKTSRSSV TP 1 Drosophila melanogaster (Fruit fly)
P57682 KLF3
KLF3_HUMAN
61 65 SHGIQMEPVDLTVNKRSSPP TP 1 Homo sapiens (Human)
P37275 ZEB1
ZEB1_HUMAN
734 738 QEEPQVEPLDLSLPKQQGEL TP 1 Homo sapiens (Human)
Q99708 RBBP8
COM1_HUMAN
490 494 GDCVMDKPLDLSDRFSAIQR TP 1 Homo sapiens (Human)
O95600 KLF8
KLF8_HUMAN
86 90 FSLPQVEPVDLSFHKPKAPL TP 1 Homo sapiens (Human)
Q03112 MECOM
EVI1_HUMAN
584 588 PATSQDQPLDLSMGSRSRAS TP 1 Homo sapiens (Human)
Please cite: The Eukaryotic Linear Motif resource: 2022 release. (PMID:34718738)

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