Kelch-like protein

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<StructureSection load='4ifl' size='340' side='right' caption='Human Kelch-like protein19 (Keap1) Kelch domain (dark green) complex with NRF2 Neh2 peptide (light green) (PDB code [[4ifl]])' scene=''>
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<StructureSection load='' size='450' side='right' caption='Human Kelch-like protein 1 (Keap1) Kelch domain (cyan) complex with NRF2 Neh2 peptide (green) and sulfate (PDB code [[1x2r]])' scene='70/706701/Cv/1'>
== Function ==
== Function ==
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'''Kelch-like proteins''' (KLHL) contain multiple Kelch motifs. This motif is about 50 residues long and forms a four-stranded β-sheet blade. Six to Eight such blades form a circular β-propeller domain. β-prepellers are involved in protein-protein interactions. The N-terminal of KLHL contains other protein domains like BTB (Broad-Tramtrack-Bric-a-brac) which is also involved in protein-protein interactions<ref>PMID:23676014</ref>.
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'''Kelch-like proteins''' (KLHL) contain multiple Kelch motifs. This motif is about 50 residues long and forms a four-stranded β-sheet blade. <scene name='70/706701/Cv/6'>Six to eight such blades form a circular β-propeller domain</scene>. β-propellers are involved in protein-protein interactions. The N-terminal of KLHL contains other protein domains like BTB (Broad-Tramtrack-Bric-a-brac) which is also involved in protein-protein interactions<ref>PMID:23676014</ref>.<br />
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*'''KLHL2''' '''KLHL11''' is a component of the cullin-RING based E3 ubiquitin-protein ligase system.<br />
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*'''KLHL3''' and '''KLHL7''' '''KLHL10''' are substrate-specific adapters of the cullin-RING based E3 ubiquitin-protein ligase system.<br />
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*'''KLHL12''' may play a role in collagen export.<br />
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*'''KLHL16 or gigaxonin''' plays a role in neurofilament architecture.<br />
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*'''KLHL19 (Keap1)''' interacts with the Neh2 peptide of NRF2.<br />
== Disease ==
== Disease ==
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Somatic mutations in Keap1 were found in lung cancer patients.
== Relevance ==
== Relevance ==
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NRF2 is a regulator of antioxidant response, hence Keap1 is investigated as a drug target.
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'''KLHL19 (Keap1)''' interacts with the Neh2 peptide of NRF2. NRF2 is a regulator of antioxidant response, hence Keap1 is investigated as a drug target.
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== Structural highlights ==
== Structural highlights ==
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The <scene name='70/706701/Cv/7'>interaction of Keap1 with Neh2 is through the first Glu in the latter's ETGE motif</scene><ref>PMID:16507366</ref>. <scene name='70/706701/Cv/8'>All interactions of Keap1 with Neh2</scene>. Water molecules shown as red spheres.
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</StructureSection>
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== 3D Structures of Kelch-like protein ==
== 3D Structures of Kelch-like protein ==
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[[Kelch-like protein 3D structures]]
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Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
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</StructureSection>
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{{#tree:id=OrganizedByTopic|openlevels=0|
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*Kelch-like protein 2
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**[[2xn4]] – hKLHL2 Kelch domain – human <br />
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*Kelch-like protein 3
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**[[4chb]], [[4ch9]] – hKLHL3 Kelch domain + serine/threonine protein kinas WNK4 peptide <br />
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**[[4hxi]] – hKLHL3 BTB-BACK domain (mutant) + cullin-3 N terminal <br />
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*Kelch-like protein 7
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**[[3ii7]] – hKLHL7 Kelch domain <br />
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*Kelch-like protein 11
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**[[3i3n]] – hKLHL11 BTB-BACK domain <br />
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**[[4ap2]], [[4apf]] – hKLHL11 BTB-BACK domain + cullin-3 N terminal <br />
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*Kelch-like protein 12
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**[[2vpj]] – hKLHL12 Kelch domain <br />
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*Kelch-like protein 16 (gigaxonin)
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**[[3hve]] – hKLHL16 <br />
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**[[2ppi]] – hKLHL16 BTB domain <br />
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*Kelch-like protein 19 (kelch-like ECH-associated protein 1; Keap1)
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**[[1u6d]], [[1zgk]], [[4ifj]] – hKeap1 Kelch domain <br />
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**[[3zgd]] – hKeap1 Kelch domain (mutant) <br />
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**[[4cxi]], [[4cxj]] – hKeap1 BTB domain (mutant) <br />
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**[[1x2j]] – mKeap1 Kelch domain - mouse <br />
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*Keap1 complex with peptide
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**[[1x2r]] – mKeap1 Kelch domain + NRF2 Neh2 peptide <br />
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**[[2z32]] – mKeap1 Kelch domain + prothymosin a peptide <br />
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**[[3ade]], [[3wdz]] – mKeap1 Kelch domain + sequestosome-1 peptide <br />
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**[[2dyh]] – mKeap1 Kelch domain + NRF2 residues 22-36 <br />
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**[[3wn7]] – mKeap1 Kelch domain + NRF2 residues 17-51 <br />
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**[[4ifl]], [[2flu]], [[3zgc]] – hKeap1 Kelch domain + NRF2 Neh2 peptide <br />
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*Keap1 complex with small molecule
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**[[3vng]], [[3vnh]] – hKeap1 Kelch domain + oxadiazole derivative <br />
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**[[4ifn]] – hKeap1 Kelch domain + quinoline derivative <br />
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**[[4l7b]], [[4l7c]], [[4l7d]] [[4n1b]] – hKeap1 Kelch domain (mutant) + quinoline derivative <br />
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**[[4in4]] – hKeap1 Kelch domain + inhibitor <br />
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**[[4iqk]] – hKeap1 Kelch domain (mutant) + inhibitor <br />
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**[[4cxt]] – hKeap1 BTB domain (mutant) + antagonist<br />
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}}
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== References ==
== References ==
<references/>
<references/>
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[[Category:Topic Page]]

Current revision

Human Kelch-like protein 1 (Keap1) Kelch domain (cyan) complex with NRF2 Neh2 peptide (green) and sulfate (PDB code 1x2r)

Drag the structure with the mouse to rotate

References

  1. ↑ Dhanoa BS, Cogliati T, Satish AG, Bruford EA, Friedman JS. Update on the Kelch-like (KLHL) gene family. Hum Genomics. 2013 May 15;7:13. doi: 10.1186/1479-7364-7-13. PMID:23676014 doi:http://dx.doi.org/10.1186/1479-7364-7-13
  2. ↑ Padmanabhan B, Tong KI, Ohta T, Nakamura Y, Scharlock M, Ohtsuji M, Kang MI, Kobayashi A, Yokoyama S, Yamamoto M. Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer. Mol Cell. 2006 Mar 3;21(5):689-700. PMID:16507366 doi:10.1016/j.molcel.2006.01.013

Proteopedia Page Contributors and Editors (what is this?)

Michal Harel, Alexander Berchansky, Joel L. Sussman

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