title: Solution structure of the WNK1 autoinhibitory domain, a WNK-specific PF2 domain.
abstract: WNK1 [with no lysine (K)-1] is a 250-kDa serine/threonine protein kinase involved in the maintenance of cellular salt levels and is directly linked to a hereditary form of hypertension. Here, we report the solution NMR structure of the autoinhibitory domain of WNK1 (WNK1-AI), a small regulatory subunit that lies immediately C-terminal of the kinase domain. We show that this domain is a homolog of the RFXV-binding PASK/FRAY homology 2 (PF2) domain found in OSR (oxidative stress responsive) and SPAK (serine/threonine proline-alanine-rich) kinases, which are substrates of WNK1. The WNK1-AI has a circularly permuted topology relative to the OSR1-PF2 domain. Nevertheless, like PF2 domains, WNK1-AI binds peptides that contain an RFXV motif with micromolar affinities as assessed by changes in (1)H,(15)N heteronuclear single quantum coherence spectra. Mutations to the WNK1-AI and binding peptides confirm a similar binding mode.
authors: Department of Pharmacology, College of Medicine, University of Vermont, 89 Beaumont Avenue, Burlington, VT 05405, USA. thomas.moon@uvm.edu
authors: Thomas M
authors: TM
authors: Moon
authors: Fernando
authors: F
authors: Correa
authors: Lisa N
authors: LN
authors: Kinch
authors: Alexander T
authors: AT
authors: Piala
authors: Kevin H
authors: KH
authors: Gardner
authors: Elizabeth J
authors: EJ
authors: Goldsmith
mesh_terms: D000595:Amino Acid Sequence; D009682:Magnetic Resonance Spectroscopy; D015778:Minor Histocompatibility Antigens; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D000076204:WNK Lysine-Deficient Protein Kinase 1
chemical_list: D015778:Minor Histocompatibility Antigens; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C410410:Wnk1 protein, rat