Autoregulation of the LIM kinases by their PDZ domain

Casanova-Sepúlveda, Gabriela; Sexton, Joel A.; Turk, Benjamin E.; Boggon, Titus J.

doi:10.1038/s41467-023-44148-4

Title: Autoregulation of the LIM kinases by their PDZ domain

Journal Article · 18 December 2023 · Nature Communications

DOI: https://doi.org/10.1038/s41467-023-44148-4 · OSTI ID:2470229

Casanova-Sepúlveda, Gabriela ^[1];

^[1];

^[1]

Yale University, New Haven, CT (United States)

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF); National Institutes of Health (NIH); American Heart Association

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2470229

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 14; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
Kinases
Science & Technology
X-ray crystallography

Title: Autoregulation of the LIM kinases by their PDZ domain

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