Schumacher FR, Sorrell FJ, Alessi DR, Bullock AN, Kurz T

With no lysine (K) kinase-1 (WNK1) 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 utilises Cullin3 (CUL3) and its ...

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substrate adaptor, kelch-like protein 3 (KLHL3). Loss of function mutations in either CUL3 or KLHL3 cause the hereditary high blood pressure disease Gordon's syndrome by stabilising 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 the kelch-like 2 (KLHL2) protein 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 kelch-like protein KEAP1 binds to its substrate NRF2. This study provides further insights into how kelch-like adaptor proteins recognise their substrates and provides a structural basis for how mutations in WNK4 and KLHL3 lead to hypertension.

Date: Mar. 18, 2014

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