<scp>LIM</scp> domain proteins in cell mechanobiology

Anderson, Caitlin A; Kovar, David R.; Gardel, Margaret L.; Winkelman, Jonathan D.

doi:10.1002/cm.21677

Cited by 44 publications

(34 citation statements)

References 96 publications

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“…The postulated dramatic conformational changes in plastins accompanied by domain separation are consistent with recognized mechanisms of mechanosensing that operate via i) dynamic "catch" and "slip" bonds 86 and ii) exposure of cryptic sites in cytoskeletal proteins 87,88 . Indeed, several indirect but strong lines of evidence support plastin's role in mechanotransduction.…”

Section: Discussionsupporting

confidence: 69%

“…Specifically, the loop 184-189 and the first five residues of the helix 190-206 of CH1 are sufficiently close to make contacts at both sides (subdomains 1 and 3) of the hydrophobic cleft of the "i" actin subunit but also with the 44-48 segment of the D-loop (subdomain 2) of the longitudinally adjacent subunit "i+2". Also, in subdomain 1 of the "i+2" subunit, the tip of [79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95] helix is in proximity to residues Gln118, Asn213, and His225 of plastin's CH1. With the exception of Asn213, all these PLS3 residues are different from those determined in a previous model based on a ~ 30-Å resolution reconstruction of ABD1-decorated actin filaments 65 .…”

Section: Abd1 Binds F-actin In a Similar To Abd2 Mode But With A Smaller Footprintmentioning

confidence: 99%

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Allosteric Regulation of Human Plastins

Schwebach

Kudryashova

Agrawal

et al. 2021

Preprint

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Plastins/fimbrins are conserved actin-bundling proteins contributing to motility, cytokinesis, and other cellular processes by organizing actin assemblies of strikingly different geometries as in aligned bundles and branched networks. We propose that this unique ability stems from an allosteric communication between plastins’ two actin-binding domains (ABD1/2) engaged in a tight spatial association. We found that although ABD1 binds actin first, ABD2 can bind to actin three orders of magnitude stronger if not inhibited by an equally strong allosteric engagement with ABD1. Binding of ABD1 to actin lessened the inhibition, enabling weak bundling within aligned bundles. A mutation mimicking physiologically relevant phosphorylation at the ABD1-ABD2 interface strongly reduced their association, dramatically potentiating actin cross-linking. Cryo-EM reconstruction revealed the ABD1-actin interface and enabled modeling of the plastin bridge to confirm domain separation in parallel bundles. The characteristic domain organization with a strong allosteric inhibition imposed by ABD1 on ABD2 allows plastins to tune cross-linking, contributing to the assembly and remodeling of actin assemblies with different morphological and functional properties defining the unique place of plastins in actin organization.

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Section: Discussionsupporting

confidence: 69%

Section: Abd1 Binds F-actin In a Similar To Abd2 Mode But With A Smaller Footprintmentioning

confidence: 99%

Allosteric Regulation of Human Plastins

Schwebach

Kudryashova

Agrawal

et al. 2021

Preprint

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“…It is well-known that the ILK-1 ankyrin repeat domain exhibits spring-like characteristics and hence elastic properties and thereby can react to forces by unfolding of its own protein domains ( Lee et al, 2006 ). In line with these results, quantitative proteomic analysis of mechanotransduction pathways in mammalian cells has identified that LIM domain proteins, such as PINCH1, which possesses five LIM domains, fulfill tasks as potential tension sensors ( Schiller et al, 2011 ; Anderson et al, 2021 ). Numerous proteins possessing a LIM domain exhibit reduced integrin-based focal adhesion or stress fiber recruitment upon actomyosin contractility inhibition ( Kuo et al, 2011 ; Schiller et al, 2011 ), implying that the LIM domains may act as a mechanical reaction unit.…”

Section: Discussionmentioning

confidence: 69%

PINCH1 Promotes Fibroblast Migration in Extracellular Matrices and Influences Their Mechanophenotype

Mierke

Hayn

Fischer

2022

Front. Cell Dev. Biol.

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Cell migration performs a critical function in numerous physiological processes, including tissue homeostasis or wound healing after tissue injury, as well as pathological processes that include malignant progression of cancer. The efficiency of cell migration and invasion appears to be based on the mechano-phenotype of the cytoskeleton. The properties of the cytoskeleton depend on internal cytoskeletal and external environmental factors. A reason for this are connections between the cell and its local matrix microenvironment, which are established by cell-matrix adhesion receptors. Upon activation, focal adhesion proteins such as PINCH1 are recruited to sites where focal adhesions form. PINCH1 specifically couples through interactions with ILK, which binds to cell matrix receptors and the actomyosin cytoskeleton. However, the role of PINCH1 in cell mechanics regulating cellular motility in 3D collagen matrices is still unclear. PINCH1 is thought to facilitate 3D motility by regulating cellular mechanical properties, such as stiffness. In this study, PINCH1 wild-type and knock-out cells were examined for their ability to migrate in dense extracellular 3D matrices. Indeed, PINCH1 wild-type cells migrated more numerously and deeper in 3D matrices, compared to knock-out cells. Moreover, cellular deformability was determined, e.g., elastic modulus (stiffness). PINCH1 knock-out cells are more deformable (compliable) than PINCH1 wild-type cells. Migration of both PINCH1−/− cells and PINCH1fl/fl cells was decreased by Latrunculin A inhibition of actin polymerization, suggesting that actin cytoskeletal differences are not responsible for the discrepancy in invasiveness of the two cell types. However, the mechanical phenotype of PINCH1−/− cells may be reflected by Latrunculin A treatment of PINCH1fl/fl cells, as they exhibit resembling deformability to untreated PINCH1−/− cells. Moreover, an apparent mismatch exists between the elongation of the long axis and the contraction of the short axis between PINCH1fl/fl cells and PINCH1−/− cells following Latrunculin A treatment. There is evidence of this indicating a shift in the proxy values for Poisson’s ratio in PINCH1−/− cells compared with PINCH1fl/fl cells. This is probably attributable to modifications in cytoskeletal architecture. The non-muscle myosin II inhibitor Blebbistatin also reduced the cell invasiveness in 3D extracellular matrices but instead caused a stiffening of the cells. Finally, PINCH1 is apparently essential for providing cellular mechanical stiffness through the actin cytoskeleton, which regulates 3D motility.

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“…There are 41 LIM (Lin-11, Isl1, and MEC-3) domain-containing proteins enriched at cell adhesions and/or the actomyosin cytoskeleton. 53 The LIM protein zyxin, which localized to stress fibres, F-actins, and AJs, was mobilized by laminar SS (15 dynes/cm 2 , 2 h) and moved from focal adhesions to F-actins. 54 …”

Section: The Cytoskeletonmentioning

confidence: 99%

Endothelial Mechanosensors for Atheroprone and Atheroprotective Shear Stress Signals

Li¹,

Zhou²,

Xia³

et al. 2022

JIR

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Vascular endothelial cells (ECs), derived from the mesoderm, form a single layer of squamous cells that covers the inner surface of blood vessels. In addition to being regulated by chemical signals from the extracellular matrix (ECM) and blood, ECs are directly confronted to complex hemodynamic environment. These physical inputs are translated into biochemical signals, dictating multiple aspects of cell behaviour and destination, including growth, differentiation, migration, adhesion, death and survival. Mechanosensors are initial responders to changes in mechanical environments, and the overwhelming majority of them are located on the plasma membrane. Physical forces affect plasma membrane fluidity and change of protein complexes on plasma membrane, accompanied by altering intercellular connections, cell-ECM adhesion, deformation of the cytoskeleton, and consequently, transcriptional responses in shaping specific phenotypes. Among the diverse forces exerted on ECs, shear stress (SS), defined as tangential friction force exerted by blood flow, has been extensively studied, from mechanosensing to mechanotransduction, as well as corresponding phenotypes. However, the precise mechanosensors and signalling pathways that determine atheroprone and atheroprotective phenotypes of arteries remain unclear. Moreover, it is worth to mention that some established mechanosensors of atheroprotective SS, endothelial glycocalyx, for example, might be dismantled by atheroprone SS. Therefore, we provide an overview of the current knowledge on mechanosensors in ECs for SS signals. We emphasize how these ECs coordinate or differentially participate in phenotype regulation induced by atheroprone and atheroprotective SS.

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LIM domain proteins in cell mechanobiology

Cited by 44 publications

References 96 publications

Allosteric Regulation of Human Plastins

Allosteric Regulation of Human Plastins

PINCH1 Promotes Fibroblast Migration in Extracellular Matrices and Influences Their Mechanophenotype

Endothelial Mechanosensors for Atheroprone and Atheroprotective Shear Stress Signals

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