Kelch-like protein 3 (KLHL3) is a substrate adaptor protein in the CUL3-KLHL3 E3 ubiquitin ligase complex. It targets WNK4 kinase 1 for ubiquitination and degradation, which in turn regulates electrolyte homeostasis []. Mutations in the KLHL3 gene cause cause pseudohypoaldosteronism type II (PHAII), which is a rare Mendelian syndrome featuring hypertension and hyperkalemia resulting from constitutive renal salt reabsorption and impaired K(+) secretion [, ]. The CUL3-KLHL3 E3 ligase complex may regulate blood pressure via its ability to interact with and ubiquitylate WNK isoforms [, ].The KLHL (Kelch-like) proteins generally have a BTB/POZ domain, a BACK domain, and five to six Kelch motifs. They constitute a subgroup at the intersection between the BTB/POZ domain and Kelch domain superfamilies. The BTB/POZ domain facilitates protein binding [], while the Kelch domain (repeats) form β-propellers. The Kelch superfamily of proteins can be subdivided into five groups: (1) N-propeller, C-dimer proteins, (2) N-propeller proteins, (3) propeller proteins, (4) N-dimer, C-propeller proteins, and (5) C-propeller proteins. KLHL family members belong to the N-dimer, C-propeller subclass of Kelch repeat proteins []. In addition to BTB/POZ and Kelch domains, the KLHL family members contain a BACK domain, first described as a 130-residue region of conservation observed amongst BTB-Kelch proteins []. Many of the Kelch-like proteins have been identified as adaptors for the recruitment of substrates to Cul3-based E3 ubiquitin ligases [, ].
