Structural and biochemical characterization of the KLHL3–WNK kinase interaction important in blood pressure regulation
Open accessAbstract
WNK1 [with no lysine (K)] and WNK4 regulate blood pressure by controlling the activity of ion co-transporters in the kidney. Groundbreaking work has revealed that the ubiquitylation and hence levels of WNK isoforms are controlled by a Cullin-RING E3 ubiquitin ligase complex (CRL3KLHL3) that utilizes CUL3 (Cullin3) and its substrate adaptor, KLHL3 (Kelch-like protein 3). Loss-of-function mutations in either CUL3 or KLHL3 cause the hereditary high blood pressure disease Gordon's syndrome by stabilizing WNK isoforms. KLHL3 binds to a highly conserved degron motif located within the C-terminal non-catalytic domain of WNK isoforms. This interaction is essential for ubiquitylation by CRL3KLHL3 and disease-causing mutations in WNK4 and KLHL3 exert their effects on blood pressure by disrupting this interaction. In the present study, we report on the crystal structure of the KLHL3 Kelch domain in complex with the WNK4 degron motif. This reveals an intricate web of interactions between conserved residues on the surface of the Kelch domain β-propeller and the WNK4 degron motif. Importantly, many of the disease-causing mutations inhibit binding by disrupting critical interface contacts. We also present the structure of the WNK4 degron motif in complex with KLHL2 that has also been reported to bind WNK4. This confirms that KLHL2 interacts with WNK kinases in a similar manner to KLHL3, but strikingly different to how another KLHL protein, KEAP1 (Kelch-like enoyl-CoA hydratase-associated protein 1), binds to its substrate NRF2 (nuclear factor-erythroid 2-related factor 2). The present study provides further insights into how Kelch-like adaptor proteins recognize their substrates and provides a structural basis for how mutations in WNK4 and KLHL3 lead to hypertension.
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Crystal structures of peptide substrate complexes have been reported for four BTB-Kelch family members, including KEAP1, KLHL2, KLHL3 and KLHL20.
“Crystal structures of peptide substrate complexes have been reported for four BTB-Kelch family members, including KEAP1, KLHL2, KLHL3 and KLHL20 (refs 80,81,82 ).”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [81]
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Ca2+is a Regulator of the WNK/OSR1/NKCC Pathway in a Human Salivary Gland Cell Line
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A tissue-specific ubiquitin switch coordinates brain, craniofacial, and skin developmentPreprint
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- Authors
- Schumacher, F.-R., Sorrell, F. J., Alessi, D. R., Bullock, A. N., & Kurz, T.
- Affiliations
- University of Dundee (GB)
- University of Oxford (GB)
- Corresponding author
- Kurz, Thimo
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2014-05-13
- Volume
- 460
- Issue
- 2
- Pages
- 237-246
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC4019986
- OpenAlex
- W2033437534
- Cited by
- 76
- References
- 53
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 3 · 2023: 6 · 2022: 12 · 2021: 4 · 2020: 7 · 2019: 8 · 2018: 5 · 2017: 5 · 2016: 6 · 2015: 10 · 2014: 2
- FWCI
- 3.13
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Biochemical Journal (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion, cc-by)
- Funders
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- GlaxoSmithKline
- Genome Canada
- Wellcome Trust (092809, 092809/Z/10/Z, 1097737, 089698)
- Diamond Light Source (1097737)
- Ontario Ministry of Economic Development and Innovation (092809/Z/10/Z)
- Ministero dello Sviluppo Economico
- Canadian Institutes of Health Research
- Medical Research Council (MC_G1000735)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- KLHL3, WNK4, WNK1, CUL3, Kelch domain, protein-protein interaction, ubiquitination, hypertension, Keap1, Nrf2, crystal structure, pathogenic variants
- MeSH terms
- WNK Lysine-Deficient Protein Kinase 1, Blood Pressure, Carrier Proteins, Crystallization, Humans, Hypertension, Microfilament Proteins, Nerve Tissue Proteins, Minor Histocompatibility Antigens, Protein Serine-Threonine Kinases, Crystallography, X-Ray, Amino Acid Motifs, Cullin Proteins, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Ubiquitination
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