DEG_Kelch_KLHL3_1

KLHL2 and KLHL3 binding degron

WNK kinases are involved in osmotic regulation and may be mutated in certain diseases that show a hypertension phenotype. An acidic degron motif is highly conserved in vertebrate WNKs and is reported to target them for destruction by the Cullin3 (Q13618) - KLHL2-3 kelch proteins, and the latter designated as E3 ligases. WNK kinases disregulated for proper destruction can cause hypertensive disease.

The CUL3 (Q13618)–KLHL3 (Q9UH77) E3 ligase complex interacts with and ubiquitylates WNK kinases, which are important for the regulation of blood pressure. The β propeller kelch domain of KLH2/3 interacts with an acidic region in the WNK kinases, which are highly conserved in vertebrates. Kelch domains (PF01344) from KLHL2 and KLHL3 in complex with WNK1/4 degron peptides show a very similar structure (4CHB and 4CH9) such that the superimposed structures have an RMSD value of 0.6 angstroms (Schumacher,2014) and both KLHL2 and KLHL3 maintain the critical residues in contact with the WNK4 peptide’s critical residues. The core degron region in WNK4 is the 11 residue long peptide 557’EPEEPEADQH’566. At the binding interface between KLHL3 and WNK4, greatest contact area is between the Arg360 of KLHL3 and four degron residues of WNK4 in 557’EPEE’560. However, the most critical contacts are between KLHL3’s Ser432 and WNK4’s Glu562 and KLHL3’s Arg528 and WNK4’s Asp564. Both interactions are most critically disrupted in Gordon’s syndrome due to Ser432Asn and Arg528His mutations in KLHL3 Kelch domain and Glu562Lys and Asp564Ala mutations in WNK4 degron motif (23073627; Wu,2013; 11498583). On the other hand Kelch domains from KLHL2 and KLHL3 bound to WNK degron peptides show a different structure compared to the Kelch domain of KEAP1 (Q14145) bound to NRF2 (Q16236) degron motif. While the binding conformation between KEAP1 and NRF2 show a sandwiched motif between Kelch domains, the same conformation is not exactly observed between Kelch domains of KLHL2/3 and WNK4. The available structures for KLHL2/3 and WNK1/4 don’t explain the conservation level of the Glutamic acid residues in the degron and the marked difference of binding dynamics compared to KEAP1 and NRF2, which await further investigation.

Kelch_1 (PF01344) Kelch motif (Stochiometry: 1 : 1)