8GI4

Crystal structure of human LIMK2 PDZ domain

Summary for 8GI4

• Entry DOI: 10.2210/pdb8gi4/pdb
• Descriptor: LIM domain kinase 2 (2 entities in total)
• Functional Keywords: pdz domain, protein kinase, autoregulation, cofilin, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 8
• Total formula weight: 109834.46

Authors

Casanova Sepulveda, G.,Boggon, T.J. (deposition date: 2023-03-13, release date: 2023-12-06, Last modification date: 2024-05-01)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.06 Å)