Enaptin, a giant actin-binding protein, is an element of the nuclear membrane and the actin cytoskeleton

Padmakumar, V. C.; Abraham, Sabu; Braune, Stephan; Noegel, Angelika A.; Tunggal, Budi; Karakesisoglou, Iakowos; Korenbaum, Elena

doi:10.1016/j.yexcr.2004.01.014

Cited by 179 publications

(199 citation statements)

References 16 publications

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“…Hence, we expect that LINC complexes of various composition form at the NE. It is important to note, however, that while Sun proteins and Nesprins are ubiquitously expressed, their relative expression levels greatly differ among tissues [9,20,24]. Therefore, the compositional nature of LINC complexes may significantly vary among tissues.…”

Section: Sun Proteins Interact Promiscuously With Nesprinsmentioning

confidence: 99%

“…Several isoforms of Nesprin 1 (also called Syne1 [18], Myne1 [19], and Enaptin [20]) and Nesprin 2 (also called Syne2 [18] and NUANCE [21]) are encoded by the alternative transcription and splicing of two distinct genes [22]. Nesprins are characterized by a variable number of spectrin repeats and most isoforms share a conserved C-terminal KASH domain (Klarsicht-Ancl-Syne1 Homology) comprising ∼50 amino acids.…”

Section: Introductionmentioning

confidence: 99%

“…While Nesprin isoforms display a complex subcellular distribution, giant Nesprin 1 (> 700 kDa) and Nesprin 2 (> 1 MDa) both localize to the ONM and extend as rod-like structures of up to 300-400 nm into the cytoplasm. Through their N-terminal actin-binding domains (ABD), giant Nesprins 1 and 2 bind to actin microfilaments [20,21,23]. Nesprin 3α and β proteins, both encoded by the alternative splicing of a separate gene, each contain a KASH domain and localize to the ONM but are more modest in size (∼100 kDa) than giant Nesprins 1 and 2.…”

Section: Introductionmentioning

confidence: 99%

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Structural requirements for the assembly of LINC complexes and their function in cellular mechanical stiffness

Stewart-Hutchinson

Hale

Wirtz

et al. 2008

Experimental Cell Research

258

295

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The evolutionary-conserved interactions between KASH and SUN domain-containing proteins within the perinuclear space establish physical connections, called LINC complexes, between the nucleus and the cytoskeleton. Here, we show that the KASH domains of Nesprins 1, 2 and 3 interact promiscuously with luminal domains of Sun1 and Sun2. These constructs disrupt endogenous LINC complexes as indicated by the displacement of endogenous Nesprins from the nuclear envelope. We also provide evidence that KASH domains most probably fit a pocket provided by SUN domains and that post-translational modifications are dispensable for that interaction. We demonstrate that the disruption of endogenous LINC complexes affect cellular mechanical stiffness to an extent that compares to the loss of mechanical stiffness previously reported in embryonic fibroblasts derived from mouse lacking A-type lamins, a mouse model of muscular dystrophies and cardiomyopathies. These findings support a model whereby physical connections between the nucleus and the cytoskeleton are mediated by interactions between diverse combinations of Sun proteins and Nesprins through their respective evolutionary-conserved domains. Furthermore, they emphasize, for the first time, the relevance of LINC complexes in cellular mechanical stiffness suggesting a possible involvement of their disruption in various laminopathies, a group of human diseases linked to mutations of A-type lamins.

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Section: Sun Proteins Interact Promiscuously With Nesprinsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structural requirements for the assembly of LINC complexes and their function in cellular mechanical stiffness

Stewart-Hutchinson

Hale

Wirtz

et al. 2008

Experimental Cell Research

258

295

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“…Members of this family, such as ANC-1 and UNC-83, have little in common with each other beyond the KASH domain. Nesprin/SYNE-1, -2, and -3 are representative members of the mammalian KASH domain protein family (20,24,25). SUN proteins are characterized by a C-terminal ϳ200 amino acid residue SUN domain that is conserved among all eukaryotes including Schizosaccharomyces pombe Sad1, Caenorhabditis elegans UNC-84 and SUN1, and five human SUN proteins (16,17,22,26,27).…”

mentioning

confidence: 99%

Structure of Sad1-UNC84 Homology (SUN) Domain Defines Features of Molecular Bridge in Nuclear Envelope

Zhou

Cai

et al. 2012

Journal of Biological Chemistry

121

136

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Background:The SUN domain mediates mechanical linkage across the nuclear envelope. Results: The structure of the SUN2 protein SUN domain was solved. The structure features important for SUN domain function were identified. Conclusion:The SUN domain forms a homotrimer. The SUN-KASH domain interaction is required for nuclear migration. Significance: The study provides insights into how the SUN protein complex functions.

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“…Furthermore, the SYNE1-4 genes give rise to a multitude of isoforms [10,11]. The presence of specific domains is responsible for their linkage to individual cytoskeletal elements, the actin filaments, microtubules or intermediate filaments [2,12–14]. The largest isoform of Nesprin-2, also known as NUANCE, is an ~ 800 kDa protein (6,885 amino acids) with an N-terminal F-actin binding domain (ABD), a rod domain composed of spectrin repeats and the C-terminal KASH domain[2].…”

Section: Introductionmentioning

confidence: 99%

Depletion of Nesprin-2 is associated with an embryonic lethal phenotype in mice

Mroß

Marko

Munck

et al. 2018

Nucleus

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Nesprin-2 is a nuclear envelope component and provides a link between cytoskeletal components of the cytoplasm and the nucleoplasm. Several isoforms are generated from its gene Syne2. Loss of the largest isoform Nesprin-2 Giant in mice is associated with a skin phenotype and altered wound healing, loss of C-terminal isoforms in mice leads to cardiomyopathies and neurological defects. Here we attempted to establish mice with an inducible knockout of all Nesprin-2 isoforms by inserting shRNA encoding sequences targeting the N- and C-terminus into the ROSA26 locus of mice. This caused early embryonic death of the animals harboring the mutant allele, which was presumably due to leaky expression of the shRNAs. Mutant embryos were only observed before E13. They had an altered appearance and were smaller in size than their wild type littermates. From this we conclude that the Nesprin-2 gene function is crucial during embryonic growth, differentiation and organogenesis.

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Enaptin, a giant actin-binding protein, is an element of the nuclear membrane and the actin cytoskeleton

Cited by 179 publications

References 16 publications

Structural requirements for the assembly of LINC complexes and their function in cellular mechanical stiffness

Structural requirements for the assembly of LINC complexes and their function in cellular mechanical stiffness

Structure of Sad1-UNC84 Homology (SUN) Domain Defines Features of Molecular Bridge in Nuclear Envelope

Depletion of Nesprin-2 is associated with an embryonic lethal phenotype in mice

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