2V3S

Structural insights into the recognition of substrates and activators by the OSR1 kinase

2V3S の概要

• エントリーDOI: 10.2210/pdb2v3s/pdb
• 分子名称: SERINE/THREONINE-PROTEIN KINASE OSR1, SERINE/THREONINE-PROTEIN KINASE WNK4, ACETATE ION, ... (4 entities in total)
• 機能のキーワード: atp-binding, kinase, magnesium, metal-binding, nucleotide-binding, phosphorylation, polymorphism, serine/threonine-protein kinase, transferase
• 由来する生物種: HOMO SAPIENS (HUMAN); 詳細
• 細胞内の位置: Cell junction, tight junction (By similarity): Q96J92
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 22113.90

構造登録者

Villa, F.,Goebel, J.,Rafiqi, F.H.,Deak, M.,Thastrup, J.,Alessi, D.R.,van Aalten, D.M.F. (登録日: 2007-06-21, 公開日: 2007-07-03, 最終更新日: 2024-05-08)

主引用文献

Villa, F.,Goebel, J.,Rafiqi, F.H.,Deak, M.,Thastrup, J.,Alessi, D.R.,Van Aalten, D.M.F.
Structural Insights Into the Recognition of Substrates and Activators by the Osr1 Kinase
Embo Rep., 8:839-, 2007

PubMed Abstract: The oxidative-stress-responsive kinase 1 (OSR1) and the STE20/SPS1-related proline/alanine-rich kinase (SPAK) are key enzymes in a signalling cascade regulating the activity of Na(+)/K(+)/2Cl(-) co-transporters (NKCCs) in response to osmotic stress. Both kinases have a conserved carboxy-terminal (CCT) domain, which recognizes a unique peptide (Arg-Phe-Xaa-Val) motif present in OSR1- and SPAK-activating kinases (with-no-lysine kinase 1 (WNK1) and WNK4) as well as its substrates (NKCC1 and NKCC2). Here, we describe the structural basis of this recognition event as shown by the crystal structure of the CCT domain of OSR1 in complex with a peptide containing this motif, derived from WNK4. The CCT domain forms a novel protein fold that interacts with the Arg-Phe-Xaa-Val motif through a surface-exposed groove. An intricate web of interactions is observed between the CCT domain and an Arg-Phe-Xaa-Val motif-containing peptide derived from WNK4. Mutational analysis shows that these interactions are required for the CCT domain to bind to WNK1 and NKCC1. The CCT domain structure also shows how phosphorylation of a Ser/Thr residue preceding the Arg-Phe-Xaa-Val motif results in a steric clash, promoting its dissociation from the CCT domain. These results provide the first molecular insight into the mechanism by which the SPAK and OSR1 kinases specifically recognize their upstream activators and downstream substrates.

PubMed: 17721439
DOI: 10.1038/SJ.EMBOR.7401048

実験手法

X-RAY DIFFRACTION (1.7 Å)