8GI4

Crystal structure of human LIMK2 PDZ domain

8GI4 の概要

• エントリーDOI: 10.2210/pdb8gi4/pdb
• 分子名称: LIM domain kinase 2 (2 entities in total)
• 機能のキーワード: pdz domain, protein kinase, autoregulation, cofilin, signaling protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 109834.46

構造登録者

Casanova Sepulveda, G.,Boggon, T.J. (登録日: 2023-03-13, 公開日: 2023-12-06, 最終更新日: 2024-05-01)

主引用文献

Casanova-Sepulveda, G.,Sexton, J.A.,Turk, B.E.,Boggon, T.J.
Autoregulation of the LIM kinases by their PDZ domain.
Nat Commun, 14:8441-8441, 2023

PubMed Abstract: LIM domain kinases (LIMK) are important regulators of actin cytoskeletal remodeling. These protein kinases phosphorylate the actin depolymerizing factor cofilin to suppress filament severing, and are key nodes between Rho GTPase cascades and actin. The two mammalian LIMKs, LIMK1 and LIMK2, contain consecutive LIM domains and a PDZ domain upstream of the C-terminal kinase domain. The roles of the N-terminal regions are not fully understood, and the function of the PDZ domain remains elusive. Here, we determine the 2.0 Å crystal structure of the PDZ domain of LIMK2 and reveal features not previously observed in PDZ domains including a core-facing arginine residue located at the second position of the 'x-Φ-G-Φ' motif, and that the expected peptide binding cleft is shallow and poorly conserved. We find a distal extended surface to be highly conserved, and when LIMK1 was ectopically expressed in yeast we find targeted mutagenesis of this surface decreases growth, implying increased LIMK activity. PDZ domain LIMK1 mutants expressed in yeast are hyperphosphorylated and show elevated activity in vitro. This surface in both LIMK1 and LIMK2 is critical for autoregulation independent of activation loop phosphorylation. Overall, our study demonstrates the functional importance of the PDZ domain to autoregulation of LIMKs.

PubMed: 38114480
DOI: 10.1038/s41467-023-44148-4

実験手法

X-RAY DIFFRACTION (2.06 Å)