Actin Mutations and Their Role in Disease

Parker, Francine; Baboolal, Thomas G.; Peckham, Michelle

doi:10.3390/ijms21093371

Cited by 57 publications

(55 citation statements)

References 103 publications

(146 reference statements)

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“…This contact can also be stabilized by KCl binding at a discrete cation binding site comprising Residues 202-206 and 285-288, 290 of adjacent filament subunits [ 58 ]. It is known that mutations in Segment 227-235 and amino acid residues in its intermolecular contact interface are often associated with myopathies characterized by damage of the contractile apparatus and destabilization of the filaments [ 27 , 61 , 62 ]. These myopathy-associated mutations in Segment 227-235 and in the intermolecular interface of this segment are shown in Figure 12 [ 61 ].…”

Section: Discussionmentioning

confidence: 99%

Myopathy-Sensitive G-Actin Segment 227-235 Is Involved in Salt-Induced Stabilization of Contacts within the Actin Filament

Gruszczynska-Biegala

Stefan

Kasprzak

et al. 2021

IJMS

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Formation of stable actin filaments, critically important for actin functions, is determined by the ionic strength of the solution. However, not much is known about the elements of the actin fold involved in ionic-strength-dependent filament stabilization. In this work, F-actin was destabilized by Cu2+ binding to Cys374, and the effects of solvent conditions on the dynamic properties of F-actin were correlated with the involvement of Segment 227-235 in filament stabilization. The results of our work show that the presence of Mg2+ at the high-affinity cation binding site of Cu-modified actin polymerized with MgCl2 strongly enhances the rate of filament subunit exchange and promotes the filament instability. In the presence of 0.1 M KCl, the filament subunit exchange was 2–3-fold lower than that in the MgCl2-polymerized F-actin. This effect correlates with the reduced accessibility of the D-loop and Segment 227-235 on opposite filament strands, consistent with an ionic-strength-dependent conformational change that modulates involvement of Segment 227-235 in stabilization of the intermonomer interface. KCl may restrict the mobility of the α-helix encompassing part of Segment 227-235 and/or be bound to Asp236 at the boundary of Segment 227-235. These results provide experimental evidence for the involvement of Segment 227-235 in salt-induced stabilization of contacts within the actin filament and suggest that they can be weakened by mutations characteristic of actin-associated myopathies.

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Section: Discussionmentioning

confidence: 99%

Myopathy-Sensitive G-Actin Segment 227-235 Is Involved in Salt-Induced Stabilization of Contacts within the Actin Filament

Gruszczynska-Biegala

Stefan

Kasprzak

et al. 2021

IJMS

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“…Residues co-ordinating inorganic phosphate ions were marked by i, and Mg 2+ ions by Mg. Residues involved in the lower cleft were marked by c. Moreover, selected structural features of actins were marked, as well as actin signature 1 (PS00406), actin signature 2 (PS00432), and actin-like signature (PS01132). Annotation of residues was taken from 16,17 .…”

Section: Comparison Of Phylogenetic Relationships Between Actin Groupmentioning

confidence: 99%

The origin of the expressed retrotransposed gene ACTBL2 and its influence on human melanoma cells’ motility and focal adhesion formation

Małek

Michrowska

Mazurkiewicz

et al. 2021

Sci Rep

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We have recently found that β-actin-like protein 2 (actbl2) forms complexes with gelsolin in human melanoma cells and can polymerize. Phylogenetic and bioinformatic analyses showed that actbl2 has a common origin with two non-muscle actins, which share a separate history from the muscle actins. The actin groups’ divergence started at the beginning of vertebrate evolution, and actbl2 actins are characterized by the largest number of non-conserved amino acid substitutions of all actins. We also discovered that ACTBL2 is expressed at a very low level in several melanoma cell lines, but a small subset of cells exhibited a high ACTBL2 expression. We found that clones with knocked-out ACTBL2 (CR-ACTBL2) or overexpressing actbl2 (OE-ACTBL2) differ from control cells in the invasion, focal adhesion formation, and actin polymerization ratio, as well as in the formation of lamellipodia and stress fibers. Thus, we postulate that actbl2 is the seventh actin isoform and is essential for cell motility.

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“…Regulation of the cytoskeleton is essential for cell dynamics, such as the maintenance of cell shape or motility (Egelman, 2004 ; Wu et al, 2016 ). Its malfunction promotes muscle weakness, cerebral arteriopathy, cardiomyopathy, and brain abnormalities (Parker et al, 2020 ). As the major cytoskeletal protein is actin, its regulation is responsible for several cellular functions, including maintenance of cellular morphology and formation of lamellipodia or filopodia (Lee and Dominguez, 2010 ).…”

Section: Introductionmentioning

confidence: 99%

Structural and Biochemical Characterization of EFhd1/Swiprosin-2, an Actin-Binding Protein in Mitochondria

Mun

Park

et al. 2021

Front. Cell Dev. Biol.

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Ca2+ regulates several cellular functions, including signaling events, energy production, and cell survival. These cellular processes are mediated by Ca2+-binding proteins, such as EF-hand superfamily proteins. Among the EF-hand superfamily proteins, allograft inflammatory factor-1 (AIF-1) and swiprosin-1/EF-hand domain-containing protein 2 (EFhd2) are cytosolic actin-binding proteins. AIF-1 modulates the cytoskeleton and increases the migration of immune cells. EFhd2 is also a cytoskeletal protein implicated in immune cell activation and brain cell functions. EFhd1, a mitochondrial fraternal twin of EFhd2, mediates neuronal and pro-/pre-B cell differentiation and mitoflash activation. Although EFhd1 is important for maintaining mitochondrial morphology and energy synthesis, its mechanism of action remains unclear. Here, we report the crystal structure of the EFhd1 core domain comprising a C-terminus of a proline-rich region, two EF-hand domains, and a ligand mimic helix. Structural comparisons of EFhd1, EFhd2, and AIF-1 revealed similarities in their overall structures. In the structure of the EFhd1 core domain, two Zn2+ ions were observed at the interface of the crystal contact, suggesting the possibility of Zn2+-mediated multimerization. In addition, we found that EFhd1 has Ca2+-independent β-actin-binding and Ca2+-dependent β-actin-bundling activities. These findings suggest that EFhd1, an actin-binding and -bundling protein in the mitochondria, may contribute to the Ca2+-dependent regulation of mitochondrial morphology and energy synthesis.

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Actin Mutations and Their Role in Disease

Cited by 57 publications

References 103 publications

Myopathy-Sensitive G-Actin Segment 227-235 Is Involved in Salt-Induced Stabilization of Contacts within the Actin Filament

Myopathy-Sensitive G-Actin Segment 227-235 Is Involved in Salt-Induced Stabilization of Contacts within the Actin Filament

The origin of the expressed retrotransposed gene ACTBL2 and its influence on human melanoma cells’ motility and focal adhesion formation

Structural and Biochemical Characterization of EFhd1/Swiprosin-2, an Actin-Binding Protein in Mitochondria

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