Kelch-like protein 3 (KLHL3)

Kelch-like protein 3 (KLHL3) is a cytoplasmic adapter protein that serves as a substrate-specific component of a cullin-3-based E3 ubiquitin ligase complex, known as CRL3KLHL3, within the ubiquitin-proteasome system[1][2][3][4][5][9]. This protein contains several domains including an N-terminal BTB domain (for CUL3 interaction), a BACK domain, and six C-terminal Kelch-like repeats (for substrate binding)[5][7][9]. KLHL3 recruits specific substrate proteins—principally kinases WNK1, WNK3, and WNK4—and promotes their ubiquitination and degradation, thereby regulating renal sodium and chloride transport via effects on the sodium-chloride cotransporter (NCC), and maintaining normal blood pressure and electrolyte balance[1][2][4][5]. Pathogenic mutations in KLHL3 disrupt these interactions and cause Pseudohypoaldosteronism type IID (Gordon’s syndrome), characterized by hypertension, hyperkalemia, and metabolic acidosis[2][4][5][6][9]. The protein is widely expressed and, along with other KLHL family members, may have additional roles in protein quality control, cellular morphology, and possibly cancer[7]. No drugs are known to selectively target KLHL3.

Other names

Kelch like family member 3KIAA1129PHA2Dkelch-like protein 3

No approved drugs directly target KLHL3, but the biological mechanism involves modulation of protein ubiquitylation, especially degradation of WNK1 and WNK4 kinases, which regulate sodium and chloride handling in the distal nephron[1][2][3][4][5][6][9].