Stabilization of the Spectrin-Like Domains of Nesprin-1α by the Evolutionarily Conserved “Adaptive” Domain

Zhong, Zhixia; Chang, Siwei A.; Kalinowski, Agnieszka; Wilson, Katherine L.; Dahl, Kris Noel

doi:10.1007/s12195-010-0121-3

Cited by 23 publications

(23 citation statements)

References 51 publications

(74 reference statements)

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“…Lastly, both WT and the LEAA mutant forms of nesprin-2 SR52-56 KASH interacted with dynactin even though the mutant form failed to interact with kinesin-1 (Figure S5B). These data are consistent with dynein and dynactin mediating MT-dependent forward nuclear recentration by interacting with a region near the C-terminus of nesprin-2 that includes SR52-53 and the “adaptive domain” [42]. …”

Section: Resultssupporting

confidence: 74%

Centrifugal Displacement of Nuclei Reveals Multiple LINC Complex Mechanisms for Homeostatic Nuclear Positioning

2017

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Summary Nuclear movement is critical for developmental events, cell polarity and migration and is usually mediated by LINC complexes connecting the nucleus to cytoskeletal elements. Compared to active nuclear movement, relatively little is known about homeostatic positioning of nuclei including whether it is an active process. To explore homeostatic nuclear positioning, we developed a method to displace nuclei in adherent cells using centrifugal force. Nuclei displaced by centrifugation rapidly recentered by mechanisms that depended on cell context. In cell monolayers with wounds oriented orthogonal to the force, nuclei were displaced toward the front and back of the cells on the two sides of the wound. Nuclei recentered from both positions, but at different rates and cytoskeletal linkage mechanisms. Rearward recentering was actomyosin-, nesprin-2G- and SUN2-dependent, whereas forward recentering was microtubule-, dynein-, nesprin-2G- and SUN1-dependent. Nesprin-2G engaged actin through its N-terminus and microtubules through a novel dynein interacting site near its C-terminus. Both activities were necessary to maintain nuclear position in uncentrifuged cells. Thus, even when not moving, nuclei are actively maintained in position by engaging the cytoskeleton through the LINC complex.

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Section: Resultssupporting

confidence: 74%

Centrifugal Displacement of Nuclei Reveals Multiple LINC Complex Mechanisms for Homeostatic Nuclear Positioning

2017

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“…3A). This region, termed the 'adaptive domain', is predicted to contain a high degree of disordered loops and coils (Zhong et al, 2010). Within this region, there is an almost invariant ∼20-residue motif predicted to be a 'hot loop' or area of high mobility (Simpson and Roberts, 2008;Zhong et al, 2010).…”

Section: Recruitment Of Exogenous Kif5b To the Nuclear Envelope Rescumentioning

confidence: 99%

Nesprins anchor kinesin-1 motors to the nucleus to drive nuclear distribution in muscle cells

2015

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During skeletal muscle development, nuclei move dynamically through myotubes in a microtubule-dependent manner, driven by the microtubule motor protein kinesin-1. Loss of kinesin-1 leads to improperly positioned nuclei in culture and in vivo. Two models have been proposed to explain how kinesin-1 functions to move nuclei in myotubes. In the cargo model, kinesin-1 acts directly from the surface of the nucleus, whereas in an alternative model, kinesin-1 moves nuclei indirectly by sliding anti-parallel microtubules. Here, we test the hypothesis that an ensemble of Kif5B motors acts from the nuclear envelope to distribute nuclei throughout the length of syncytial myotubes. First, using an inducible dimerization system, we show that controlled recruitment of truncated, constitutively active kinesin-1 motors to the nuclear envelope is sufficient to prevent the nuclear aggregation resulting from depletion of endogenous kinesin-1. Second, we identify a conserved kinesin light chain (KLC)-binding motif in the nuclear envelope proteins nesprin-1 and nesprin-2, and show that recruitment of the motor complex to the nucleus via this LEWD motif is essential for nuclear distribution. Together, our findings demonstrate that the nucleus is a kinesin-1 cargo in myotubes and that nesprins function as nuclear cargo adaptors. The importance of achieving and maintaining proper nuclear position is not restricted to muscle fibers, suggesting that the nesprin-dependent recruitment of kinesin-1 to the nuclear envelope through the interaction of a conserved LEWD motif with kinesin light chain might be a general mechanism for cell-typespecific nuclear positioning during development.

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“…Multiple isoforms of the large transmembrane nesprins (also called SYNEs and MYNEs) extend from the outer nuclear membrane and attach to cytoskeletal filaments. There are four known mammalian nesprin proteins, all of which contain spectrinlike repeat subunits and KASH domains (Zhong et al, 2010a). These different nesprin types also have multiple isoforms based on the number of subunits, denoted , , ,  and so on (Warren et al, 2005).…”

Section: Connections Between the Nucleoskeleton And The Cytoskeletonmentioning

confidence: 99%

Nucleoskeleton mechanics at a glance

Dahl

Kalinowski

2011

Journal of Cell Science

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The nucleus contains the genetic information of the cell and all of the regulatory factors that process the genome effectively. The genome is encapsulated by a dense, filamentous meshwork called the nucleoskeleton, which is located at the inner nuclear membrane. The components of the nucleoskeleton are involved in cellular signaling (Wilson and Berk, 2010), but they are also necessary for maintaining nuclear structure, preventing rupture of the nucleus under force and possibly assisting in force transduction (Wang et al., 2009). Here, we present the integrated mechanical structures of the nucleoskeleton, including lamin filaments, multisubunit proteins, short actin filaments and the genome. We also discuss the integration of mechanical elements from the cytoskeleton into the nucleoskeleton. Based on the mechanical contributions of the individual elements, we demonstrate how mutations in nuclear structures might impact force-dependent etiologies of disease. The accompanying poster aims to provide a translational overview between the cell biology of the nucleus and the biophysics of its underlying polymeric structures.

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Stabilization of the Spectrin-Like Domains of Nesprin-1α by the Evolutionarily Conserved “Adaptive” Domain

Cited by 23 publications

References 51 publications

Centrifugal Displacement of Nuclei Reveals Multiple LINC Complex Mechanisms for Homeostatic Nuclear Positioning

Centrifugal Displacement of Nuclei Reveals Multiple LINC Complex Mechanisms for Homeostatic Nuclear Positioning

Nesprins anchor kinesin-1 motors to the nucleus to drive nuclear distribution in muscle cells

Nucleoskeleton mechanics at a glance

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