UNC-83 Is a KASH Protein Required for Nuclear Migration and Is Recruited to the Outer Nuclear Membrane by a Physical Interaction with the SUN Protein UNC-84

McGee, Matthew D.; Rillo, Regina; Anderson, Amy; Starr, Daniel A.

doi:10.1091/mbc.e05-09-0894

Cited by 127 publications

(182 citation statements)

References 34 publications

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“…McGee et al (18) studied the interactions between UNC-83 and UNC-84 in C. elegans and suggested that the consensus sequence in KASH domain required for SUN domain association is FXPXXXYXNGPPPX. The structure of the KASH domain luminal part (KASH-LD) using the three-dimensional structures of the homologous fragments provided in the Protein Data Bank was modeled and revealed that the structure of KASH-LD consists of two mini helices followed by a C-shaped loop (C-loop) at the C terminus.…”

Section: Discussionmentioning

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

117

133

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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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Section: Discussionmentioning

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

117

133

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“…Although most likely reside in the INM, several ONM proteins have been identified (7). These include members of the mammalian nesprin (or syne) family (8,9), Klarsicht (10) and Msp-300 (11,12) in Drosophila melanogaster, Anc-1 (13), Zyg-12 (14) and Unc-83 (15,16) in Caenorhabditis elegans, and Kms2 in the fission yeast Schizosaccharomyces pombe (17). A property that each of these has in common is that they interact with cytoskeletal components.…”

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confidence: 99%

Nesprin 4 is an outer nuclear membrane protein that can induce kinesin-mediated cell polarization

Roux

Crisp

Liu

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

311

340

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Nucleocytoplasmic coupling is mediated by outer nuclear membrane (ONM) nesprin proteins and inner nuclear membrane Sun proteins. Interactions spanning the perinuclear space create nesprin-Sun complexes connecting the cytoskeleton to nuclear components. A search for proteins displaying a conserved C-terminal sequence present in nesprins 1-3 identified nesprin 4 (Nesp4), a new member of this family. Nesp4 is a kinesin-1-binding protein that displays Sun-dependent localization to the ONM. Expression of Nesp4 is associated with dramatic changes in cellular organization involving relocation of the centrosome and Golgi apparatus relative to the nucleus. These effects can be accounted for entirely by Nesp4's kinesin-binding function. The implication is that Nesp4 may contribute to microtubule-dependent nuclear positioning.centrosome ͉ LINC complex ͉ nuclear envelope T he nuclear envelope (NE) forms the interface between the nucleus and cytoplasm acting as a selective barrier that regulates nucleo-cytoplasmic traffic (1). In addition to this partition function, accumulating evidence reveals an essential role for the NE as a determinant of higher-order nuclear and chromatin organization (2). More surprising are findings that the NE directly impacts cytoskeletal architecture and in this way may help define the mechanical properties of the cell as a whole (3). The molecular bases for these effects are now emerging, uniting aspects of cellular physiology from mechanotransduction to nuclear positioning during differentiation and development (4).The NE is assembled from several elements, the most prominent being inner nuclear membranes (INMs) and outer nuclear membranes (ONMs) separated by a Ϸ40-nm gap or perinuclear space (PNS). The INM and ONM are joined where they are spanned by nuclear pore complexes (NPCs), the mediators of trafficking across the NE. The ONM also displays connections to the peripheral endoplasmic reticulum (ER). Accordingly, the INM, ONM, and ER represent a single membrane system with the PNS forming an extension of the ER lumen.The final feature of the NE is the nuclear lamina, a protein meshwork composed primarily of A-and B-type lamins that lines the nuclear face of the INM (2). The lamina is required for NE integrity and provides chromatin-anchoring sites at the nuclear periphery. Remarkably, aberrant A-type lamin expression, which is linked to several human diseases (5), is associated with altered cytoskeletal mechanics (3). The mechanisms underlying this phenomenon represent an intriguing biological problem.At least 60 NE membrane proteins are known (6). Although most likely reside in the INM, several ONM proteins have been identified (7). These include members of the mammalian nesprin (or syne) family (8, 9), Klarsicht (10) and 12) in Drosophila melanogaster, Anc-1 (13), and 16) in Caenorhabditis elegans, and Kms2 in the fission yeast Schizosaccharomyces pombe (17). A property that each of these has in common is that they interact with cytoskeletal components. They are also united in possessing a...

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“…In C. elegans, UNC-84 has been shown to recruit KASH proteins ANC-1 and UNC-83 to the outer NE for critical functions in both nuclear anchorage and nuclear migration (10,12,13). The conserved KASH domain of UNC-83 physically interacts with the SUN domain of UNC-84 in the lumen of NE (14). Similarly, in flies, the SUN protein Klaroid is required for the localization of KASH protein Klarsicht to the NE and for nuclear migration in the eye (15).…”

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confidence: 99%

SUN1 and SUN2 play critical but partially redundant roles in anchoring nuclei in skeletal muscle cells in mice

Lei

Zhang

Ding

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

219

234

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How the nuclei in mammalian skeletal muscle fibers properly position themselves relative to the cell body is an interesting and important cell biology question. In the syncytial skeletal muscle cells, more than 100 nuclei are evenly distributed at the periphery of each cell, with 3-8 nuclei anchored beneath the neuromuscular junction (NMJ). Our previous studies revealed that the KASH domain-containing Syne-1/Nesprin-1 protein plays an essential role in anchoring both synaptic and nonsynaptic myonuclei in mice. SUN domain-containing proteins (SUN proteins) have been shown to interact with KASH domain-containing proteins (KASH proteins) at the nuclear envelope (NE), but their roles in nuclear positioning in mice are unknown. Here we show that the synaptic nuclear anchorage is partially perturbed in Sun1, but not in Sun2, knockout mice. Disruption of 3 or all 4 Sun1/2 wild-type alleles revealed a gene dosage effect on synaptic nuclear anchorage. The organization of nonsynaptic nuclei is disrupted in Sun1/2 doubleknockout (DKO) mice as well. We further show that the localization of Syne-1 to the NE of muscle cells is disrupted in Sun1/2 DKO mice. These results clearly indicate that SUN1 and SUN2 function critically in skeletal muscle cells for Syne-1 localization at the NE, which is essential for proper myonuclear positioning.KASH domain ͉ Nesprin ͉ neuromuscular junction ͉ nuclear envelope protein ͉ Syne-1 P roper nuclear positioning relative to the cell body is important for many cellular processes during animal development. Mammalian skeletal muscle fibers are giant syncytial cells, each containing more than 100 nuclei. Each muscle fiber contains a neuromuscular junction (NMJ) that starts to form at approximately embryonic day 14 (E14) in mice (1). Following a multistep process involving the function of the agrin-MuSK-rapsynAChR pathway, the motor nerve terminal and the postsynaptic membrane become highly differentiated, ensuring reliable terminal transmission. The nuclei in the muscle fibers are positioned in a nonrandom manner, with 3-8 nuclei (synaptic nuclei) clustered beneath each NMJ and other nuclei (nonsynaptic nuclei) distributed evenly along the cell membrane (1, 2). How synaptic and nonsynaptic nuclei properly position themselves within each muscle fiber and the consequences of disrupting the nuclear positioning are attractive problems to investigate. Recent studies have indicated that KASH (Klarsicht/ANC-1/Syne homologue) domain-containing and SUN domain-containing proteins (KASH/SUN proteins) form a complex at the nuclear envelope (NE) for various cellular functions (3-6). Whereas a mammalian KASH protein has been found to have a critical function in myonuclear anchorage (7-9), the roles of SUN proteins in this process remain unclear.The SUN domain was first defined as a domain of shared homology between Sad1 in Schizosaccharomyces pombe and UNC-84 in Caenorhabditis elegans (10). SUN proteins are conserved inner nuclear membrane proteins containing at least 1 transmembrane domain and a C-terminal SUN...

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UNC-83 Is a KASH Protein Required for Nuclear Migration and Is Recruited to the Outer Nuclear Membrane by a Physical Interaction with the SUN Protein UNC-84

Cited by 127 publications

References 34 publications

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

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

Nesprin 4 is an outer nuclear membrane protein that can induce kinesin-mediated cell polarization

SUN1 and SUN2 play critical but partially redundant roles in anchoring nuclei in skeletal muscle cells in mice

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