Fig. 1
From: The WNK signaling pathway and salt-sensitive hypertension
Structures of the with-no-lysine kinase (WNK) signaling pathway components. a The conserved C-terminal (CCT) domain of oxidative stress-responsive gene 1 (OSR1)/Ste20-related proline–alanine–rich kinase (SPAK) interacts with the motif (RFxV/I) to bind WNK kinases and Na/Cl cotransporter (NCC). Upon this interaction, WNK kinases phosphorylate OSR1/SPAK at one threonine residue in the kinase domain and one serine residue in the S-motif. OSR1/SPAK phosphorylates NCC at three residues (T53, T58, and S71) in the N-terminal cytoplasmic domain. WNK kinases have a conserved Cl− binding pocket in the kinase domain. The PHAII-causing mutation D561A is located within the acidic motif of WNK4. b Interaction between WNK kinases, Kelch-like 3 (KLHL3), and Cullin 3 (CUL3). KLHL3 and CUL3 comprise the E3 ubiquitin ligase complex. The PHAII-causing mutation R528H is located within the Kelch repeat in KLHL3, which interacts with the acidic motif in WNK kinases. The BTB domain of KLHL3 binds to the N-terminus of CUL3. Exon 9-deleted mutant CUL3 has low affinity for the COP9 signalosome (CSN), leading to aberrant neddylation. CUL3 interacts with the ubiquitin-conjugated E2 enzyme via RING-box protein 1 (RBX1), catalyzing ubiquitin transfer to WNK kinases
