Disease-causing mutation in α-actinin-4 promotes podocyte detachment through maladaptation to periodic stretch

Feng, Di; Notbohm, Jacob; Benjamin, Ava; He, Shijie; Wang, Minxian; Ang, Lay‐Hong; Bantawa, Minaspi; Bouzid, Mehdi; Gado, Emanuela Del; Krishnan, Ramaswamy; Pollak, Martin R.

doi:10.1073/pnas.1717870115

Cited by 55 publications

(54 citation statements)

References 43 publications

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“…The balance between ACTN1 and ACTN4 expression levels can lead to different forms of cancer (Sen et al, 2009). A mutant form of ACTN4 which shows a higher affinity to actin as compared to the wild-type isoform, or an increase of ACTN4 concentration, can both lead to focal segmental glomerulosclerosis and renal failure (Feng et al, 2018;Ward et al, 2008). More surprisingly, the same phenotype could be observed in ACTN4 knock-out mice and in humans arboring ACTN4 mutation leading to the expression of an unstable form of the protein (Kos et al, 2003;Bartram et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Spatial integration of mechanical forces by alpha-actinin establishes actin network symmetry

Senger

Pitaval

Ennomani

et al. 2019

Preprint

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Cell and tissue morphogenesis depend on the production and spatial organization of tensional forces in the actin cytoskeleton. Actin network architecture is complex because it is made of distinct modules in which filaments adopt a variety of organizations. The assembly and dynamics of these modules is well described but the self-organisation rules directing the global network architecture are much less understood. Here we investigated the mechanism regulating the interplay between network architecture and the geometry of cell's extracellular environment. We found that α-actinin, a filament crosslinker, is essential for network symmetry to be consistent with extracellular microenvironment symmetry. It appeared to be required for the interconnection of transverse arcs with radial fibres to ensure an appropriate balance between forces at cell adhesions and across the entire actin network. Furthermore, the connectivity of the actin network appeared necessary for the cell ability to integrate and adapt to complex patterns of extracellular cues as they migrate. Altogether, our study has unveiled a role of actin-filament crosslinking in the physical integration of mechanical forces throughout the entire cell, and the role of this integration in the establishment and adaptation of intracellular symmetry axes in accordance with the geometry of extracellular cues.

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Section: Discussionmentioning

confidence: 99%

Spatial integration of mechanical forces by alpha-actinin establishes actin network symmetry

Senger

Pitaval

Ennomani

et al. 2019

Preprint

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“…The ability for small differences in sequence to have a significant impact on biological function is particularly clear in disease-associated CH1-CH2 mutations. Mutations to the CH1-CH2 domain of α-actinin-4 are associated with Focal Segmental Glomerulosclerosis, a kidney disorder (Weins et al, 2007;Ehrlicher et al, 2015;Feng et al, 2018), while mutations to the CH1-CH2 domain of filamin's isoforms and dystrophin are associated with Skeletal Dysplasia Krakow et al, 2004), Muscular Dystrophy (Norwood et al, 2000), and the migratory disorder Periventricular Nodular Heterotopia (PVNH) (Parrini et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Steric Regulation of Tandem Calponin Homology Domain Actin-Binding Affinity

Harris¹,

Belardi²,

Jreij³

et al. 2019

Preprint

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Tandem calponin homology domains are common actin-binding motifs found in proteins such as α-actinin, filamin, utrophin, and dystrophin that organize actin filaments into functional structures. Despite a conserved structural fold and regions of high sequence similarity, tandem calponin homology (CH1-CH2) domains can have remarkably different actin-binding properties, with disease-associated point mutants known to cause increased as well as decreased affinity for f-actin. How small variations in sequence can lead to significant differences in binding affinity and resulting actin organization remains unclear. Here, we show that the affinity of CH1-CH2 domains for f-actin can be both increased and decreased by diverse modifications that change the effective 'openness' of CH1 and CH2 that sterically regulates binding to f-actin. We find that mutations to the interdomain linker, as well as changes to the inter-CH domain interface distinct from a well characterized cationπ interaction, 'open' the domain and increases binding affinity, while a modification that adds molecular size to the CH2 'closes' the domain and decreases binding affinity. Interestingly, we observe non-uniform sub-cellular localization of CH1-CH2 domains to f-actin that depend on the N-terminal flanking region of CH1 but not on the overall affinity to f-actin. This dependence of CH1-CH2 binding properties on sequence and 'openness' contributes to a mechanistic understanding of disease-associated mutations and has implications for engineering actin-binding domains with specific properties.

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“…We show that less that one minute of network growth is enough to obtain a stabilization of the tubular structure of the membrane that is robust and lasts for tens of minutes. At smaller sleeve thicknesses, 35 discontinuous regions appear and smaller tube radii are observed in portions where the actin sleeve is absent. Therefore we never observe actin-induced scission of these membrane tubes, but rather, actin provides a way of modulating the radius of tubes along their length.…”

Section: Moreover Experiments On Living Cells Show That the Actin Cymentioning

confidence: 98%

“…To determine the network mechanical response, each monomer configuration can be submitted to a series of incremental strain steps (35,36). In each step we 530 increase the cumulative deformation strain by an amount δγ = x− x 0…”

Section: Uniaxial Deformationmentioning

confidence: 99%

Actin modulates shape and mechanics of tubular membranes

Allard

Bouzid

Betz³

et al. 2019

Preprint

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The actin cytoskeleton shapes cells and also organizes internal membranous compartments. In particular, it interacts with membranes in intracellular transport of material in mammalian cells, yeast or plant cells. Tubular membrane intermediates, pulled along microtubule tracks, are involved during these processes, and destabilize into vesicles. While the role of actin in this destabilization process is still debated, literature also provide examples of membranous structures stabilization by actin. To directly address this apparent contradiction, we mimic the geometry of tubular intermediates with preformed membrane tubes. The growth of an actin sleeve at the tube surface is monitored spatio-temporally. Depending on network cohesiveness, actin is able to stabilize, or maintain membrane tubes under pulling. Indeed, on a single tube, thicker portions correlate with the presence of actin. Such structures relax over several minutes, and may provide enough time and curvature geometries for other proteins to act on tube stability.

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Disease-causing mutation in α-actinin-4 promotes podocyte detachment through maladaptation to periodic stretch

Cited by 55 publications

References 43 publications

Spatial integration of mechanical forces by alpha-actinin establishes actin network symmetry

Spatial integration of mechanical forces by alpha-actinin establishes actin network symmetry

Steric Regulation of Tandem Calponin Homology Domain Actin-Binding Affinity

Actin modulates shape and mechanics of tubular membranes

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