4ch9

Structural highlights

Disease

[KLHL3_HUMAN] Pseudohypoaldosteronism type 2D. The disease is caused by mutations affecting the gene represented in this entry.

Function

[KLHL3_HUMAN] Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a regulator of ion transport in the distal nephron. The BCR(KLHL3) complex acts by mediating ubiquitination of WNK4, an inhibitor of potassium channel KCNJ1, leading to WNK4 degradation.^{[1] [2] [3] [4] [5] [6]}

See Also

• Kelch-like protein 3D structures

References

1. ↑ Furukawa M, He YJ, Borchers C, Xiong Y. Targeting of protein ubiquitination by BTB-Cullin 3-Roc1 ubiquitin ligases. Nat Cell Biol. 2003 Nov;5(11):1001-7. Epub 2003 Oct 5. PMID:14528312 doi:10.1038/ncb1056
2. ↑ Ohta A, Schumacher FR, Mehellou Y, Johnson C, Knebel A, Macartney TJ, Wood NT, Alessi DR, Kurz T. The CUL3-KLHL3 E3 ligase complex mutated in Gordon's hypertension syndrome interacts with and ubiquitylates WNK isoforms: disease-causing mutations in KLHL3 and WNK4 disrupt interaction. Biochem J. 2013 Apr 1;451(1):111-22. doi: 10.1042/BJ20121903. PMID:23387299 doi:http://dx.doi.org/10.1042/BJ20121903
3. ↑ Wakabayashi M, Mori T, Isobe K, Sohara E, Susa K, Araki Y, Chiga M, Kikuchi E, Nomura N, Mori Y, Matsuo H, Murata T, Nomura S, Asano T, Kawaguchi H, Nonoyama S, Rai T, Sasaki S, Uchida S. Impaired KLHL3-mediated ubiquitination of WNK4 causes human hypertension. Cell Rep. 2013 Mar 28;3(3):858-68. doi: 10.1016/j.celrep.2013.02.024. Epub 2013, Feb 28. PMID:23453970 doi:http://dx.doi.org/10.1016/j.celrep.2013.02.024
4. ↑ Wu G, Peng JB. Disease-causing mutations in KLHL3 impair its effect on WNK4 degradation. FEBS Lett. 2013 Jun 19;587(12):1717-22. doi: 10.1016/j.febslet.2013.04.032. Epub , 2013 May 9. PMID:23665031 doi:http://dx.doi.org/10.1016/j.febslet.2013.04.032
5. ↑ Shibata S, Zhang J, Puthumana J, Stone KL, Lifton RP. Kelch-like 3 and Cullin 3 regulate electrolyte homeostasis via ubiquitination and degradation of WNK4. Proc Natl Acad Sci U S A. 2013 May 7;110(19):7838-43. doi:, 10.1073/pnas.1304592110. Epub 2013 Apr 1. PMID:23576762 doi:http://dx.doi.org/10.1073/pnas.1304592110
6. ↑ Louis-Dit-Picard H, Barc J, Trujillano D, Miserey-Lenkei S, Bouatia-Naji N, Pylypenko O, Beaurain G, Bonnefond A, Sand O, Simian C, Vidal-Petiot E, Soukaseum C, Mandet C, Broux F, Chabre O, Delahousse M, Esnault V, Fiquet B, Houillier P, Bagnis CI, Koenig J, Konrad M, Landais P, Mourani C, Niaudet P, Probst V, Thauvin C, Unwin RJ, Soroka SD, Ehret G, Ossowski S, Caulfield M, Bruneval P, Estivill X, Froguel P, Hadchouel J, Schott JJ, Jeunemaitre X. KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron. Nat Genet. 2012 Mar 11;44(4):456-60, S1-3. doi: 10.1038/ng.2218. PMID:22406640 doi:http://dx.doi.org/10.1038/ng.2218