LIM domain proteins in cell mechanobiology

Abstract

The actin cytoskeleton is important for maintaining mechanical homeostasis in adherent cells, largely through its regulation of adhesion and cortical tension. The LIM (Lin-11, Isl1, MEC-3) domain-containing proteins are involved in a myriad of cellular mechanosensitive pathways. Recent work has discovered that LIM domains bind to mechanically stressed actin filaments, suggesting a novel and widely conserved mechanism of mechanosensing. This review summarizes the current state of knowledge of LIM protein mechanosensitivity.

Keywords: LIM proteins; actin cytoskeleton; adherens junctions; focal adhesions.

FIGURE 1

Mechanically stressed cells and LIM domain proteins. (a) Schematic of a layer of epithelial cells on top of an extracellular matrix (ECM). (b) Simple schematic of a LIM domain: Two zinc finger motifs. The magenta circles represent the well-conserved residues (typically cysteine or histidine) that chelate the zinc molecules. The remaining amino acid sequence varies between LIM domains. (c) Domain organization of the 14 classes of LIM domain proteins. Magenta ovals represent individual LIM domains. Dotted lines are used to abbreviate a few rather long structures. Other domain abbreviations: LD, Leucine rich aspartate domains; PET, prickle, espinas, testin; PDZ, membrane anchoring domain; HP, headpiece domain for F-actin binding; M, Myo5B interacting domain; N, nebulin; SH3, Src homology 3; CH, calponin homology; HB, homeobox. (d) Venn diagram showing the overlap of LIM domain proteins that associate with the three main networks: FA, Focal adhesions; AJ, adhesion junctions; SF, stress fibers

FIGURE 2

Schematic of LIM domain protein localization in cells. (a) Nuclear shuttling of LIM domain proteins (magenta ovals) occurs when cells spread out on stiff matrices. (b) LIM domain proteins (black and magenta ovals) localize to FAs and SFs under high tension. A subset of LIM domain proteins localizes to stress fiber strain sites (SFSS)

FIGURE 3

Schematic of mechanosensitive LCR localization to stressed actin filaments. The constitutive actin binding CRP class LIM proteins bind actin filaments in the absence or presence of force. The dashed lines indicate that CRP localization is suspected to occur for stressed actin filaments but has not been fully investigated. Mechanosensitive LIM domain protein LCR constructs bind with high affinity to actin filaments under tension or compression but with low affinity to relaxed filaments (adapted from Winkelman et al., 2020)

FIGURE 4

Evolution of LIM domain proteins. LIM domains have evolved over time to become mechanosensitive. The family then expanded to include a diverse population of proteins in mammals (adapted from Winkelman et al., 2020)