The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Functional site class:
KEAP1 binding degron
Functional site description:
Cellular response against oxidative or electrophilic attack is regulated by the action of a cytoprotective mechanism that functions via the KEAP1 (Q14145)-Nrf2 (Q16236) pathway. This mechanism is conserved from fly to human. The turnover of Nrf2 is maintained by the E3 ligase KEAP1-mediated proteasomal degradation via a two-site substrate recognition mechanism, in which two kelch domains (PF01344) of KEAP1 homodimer associate with one molecule of Nrf2 by a hinge and latch mechanism. The Kelch beta-propeller domain in KEAP1 is a protein hub in oxidative stress response pathway and it recognizes high and low affinity degron motifs in its binding partners. KEAP1-mediated substrate recognition is important for the elimination of its substrate over-activation or otherwise it may be the cause of diseases such as cancer.
ELMs with same func. site: DEG_Kelch_Keap1_1  DEG_Kelch_Keap1_2 
ELM Description:
This is the primary and higher affinity site. The interaction network of KEAP1 (Q14145) contains a significant number of associated proteins with the high affinity motif, which make strong and specific interaction with the β-propeller structure of Kelch domain (PF01344), forming many electrostatic interactions. All of the high affinity motifs form β hairpin structures and have similar modes of interaction. The binding pocket of KEAP1 contains multiple charged and hydrophobic residues that contact the side chains of two glutamate residues and the peptide backbone. The beta-hairpin structure of the motif is stabilized by aspartate and threonine residues. Phosphorylation of the threonine residue prevents binding of the peptide to KEAP1. The motif is highly conserved from fly to human.
Pattern: [DNS].[DES][TNS]GE
Pattern Probability: 0.0000595
Present in taxon: Metazoa
Interaction Domain:
Kelch_1 (PF01344) Kelch motif (Stochiometry: 1 : 1)
o See 13 Instances for DEG_Kelch_Keap1_1
o Abstract
Oxidative and xenobiotic stresses affect the cellular homeostasis and are responsible for the development of many diseases, including cancer, cardiovascular disease, diabetes, and neurodegeneration. The cellular defence mechanism against the oxidative stress and electrophilic attack referred to as “cytoprotective response” is obtained by the action of an array of genes encoding detoxifying and anti-oxidative stress enzymes. A Cap N’ Collar (CNC) family transcription factor Nrf2 and its homologues act as major regulators of cytoprotective gene expression (Kobayashi,2002). The level of Nrf2 (Q16236) in the cell is modulated mainly by its interaction with the KEAP1 protein (Q14145). One Nrf2 molecule interacts with two molecules of KEAP1 via two binding sites, the stronger binding motif and the weaker binding motif. Under unstressed conditions, KEAP1 Kelch domain (PF01344) binds to the degron motifs in Nrf2 and promote its ubiquitin dependent degradation. When cells are exposed to oxidative stress, the conformational changes in KEAP1 allow the high affinity motif to be attached to the KEAP1, acting as a hinge of the KEAP1 repression gate. On the other hand, the DLG motif acts as a latch, resulting in the detachment of low affinity motif from KEAP1 and escape protein degradation driving the expression of genes encoding detoxifying and anti-oxidative stress enzymes (24024136).
KEAP1 is a crucial hub in the oxidative stress responsive pathway and apoptosis (Hast,2013). It acts as a substrate adaptor protein for a Cul3 (Q13618)-dependent E3 ubiquitin ligase. Many of its interacting partners compete with Nrf2 for KEAP1 interaction. They all bind to the same bottom region of the propeller domain of KEAP1 with varying affinities (Padmanabhan,2006). Although there is no obvious sequence similarity between the high and low affinity binding motifs, the residues that are largely buried in the Kelch domain binding interface all have similar φ and ψ dihedral angles. The high affinity motif is present in a higher number of proteins. The low affinity motif, which have been so far identified in only Nrf2 (Q60795) and apoptotic protein Bcl2 (P10417).
o 10 selected references:

o 12 GO-Terms:

o 13 Instances for DEG_Kelch_Keap1_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
Q64337 Sqstm1
349 354 HLSSKEVDPSTGELQSLQMP TP 7 Mus musculus (House mouse)
P26350 Ptma
41 46 PANGNAQNEENGEQEADNEV TP 6 Mus musculus (House mouse)
Q12830 BPTF
729 734 ESAKAADDPENGERESHTPV TP 2 Homo sapiens (Human)
Q13402 MYO7A
1636 1641 KGDLIILDHDTGEQVMNSGW TP 1 Homo sapiens (Human)
89 94 LHIKTHLDEETGEKTSITLD TP 4 Homo sapiens (Human)
286 291 SSLEEPHSPETGEKVVAGEV TP 6 Homo sapiens (Human)
O14920 IKBKB
34 39 GNVIRWHNQETGEQIAIKQC TP 4 Homo sapiens (Human)
Q96HS1-1 PGAM5
77 82 LINVRKRNVESGEEELASKL TP 2 Homo sapiens (Human)
Q13501 SQSTM1
347 352 HLSSKEVDPSTGELQSLQMP TP 4 Homo sapiens (Human)
P20482 cnc
458 463 NGIPFTIDNETGEYIRLPLD TP 1 Drosophila melanogaster (Fruit fly)
Q14494 NFE2L1
231 236 LARNLLVDGETGESFPAQVP TP 1 Homo sapiens (Human)
Q16236 NFE2L2
77 82 FFAQLQLDEETGEFLPIQPA TP 4 Homo sapiens (Human)
Q60795 Nfe2l2
77 82 FFAQFQLDEETGEFLPIQPA TP 6 Mus musculus (House mouse)
Please cite: The Eukaryotic Linear Motif resource: 2022 release. (PMID:34718738)

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