Molecular Insights into the Mechanisms of SUN1 Oligomerization in the Nuclear Envelope

Jahed, Zeinab; Fadavi, Darya; Vu, Uyen T.; Asgari, Ehsaneddin; Luxton, G. W. Gant; Mofrad, Mohammad R. K.

doi:10.1016/j.bpj.2018.01.015

Cited by 40 publications

(39 citation statements)

References 65 publications

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“…In C. elegans, immunostaining of UNC-84 and UNC-83 shows punctate distribution of LINC complexes on the nuclear envelope during nuclear migration [21,22]. SUN1 punctate are also observed in Hela cells [43][44][45]. Another case for higher-order organization of LINC complex involves how nuclei move rearward in wounded NIH3T3 fibroblasts.…”

Section: Other Factors That Influence Force Transmission Through Lincmentioning

confidence: 99%

“…SUN1 has also been observed to form clusters in a reconstituted, cell-free expression system on artificial lipid bilayers [41]. Computer modeling predicts that SUN1 trimers can associate with each other laterally through their SUN domains to form higher-order clusters [41,43]. It has also been proposed that a cysteine adjacent to the SUN domain of SUN1 protein is able to form intermolecular disulfide bonds with neighboring SUN trimers [44,50].…”

Section: Other Factors That Influence Force Transmission Through Lincmentioning

confidence: 99%

“…It has also been proposed that a cysteine adjacent to the SUN domain of SUN1 protein is able to form intermolecular disulfide bonds with neighboring SUN trimers [44,50]. The specific requirement of mammalian SUN1, but not SUN2, during meiotic chromosome pairing, might be associated with the ability of SUN1 to more easily form higher-order structures than SUN2 [9,43,44,49]. Interestingly, a recent study has shown different mechanisms involved in homeostatic nuclear positioning under centrifugal force.…”

Section: Other Factors That Influence Force Transmission Through Lincmentioning

confidence: 99%

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SUN/KASH interactions facilitate force transmission across the nuclear envelope

Hao

Starr

2019

Nucleus

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LINC complexes (Linker of Nucleoskeleton and Cytoskeleton), consisting of inner nuclear membrane SUN (Sad1, UNC-84) proteins and outer nuclear membrane KASH (Klarsicht, ANC-1, and Syne Homology) proteins, are essential for nuclear positioning, cell migration and chromosome dynamics. To test the in vivo functions of conserved interfaces revealed by crystal structures, Cain et al used a combination of Caenorhabditis elegans genetics, imaging in cultured NIH 3T3 fibroblasts, and Molecular Dynamic simulations, to study SUN-KASH interactions. Conserved aromatic residues at the -7 position of the C-termini of KASH proteins and conserved disulfide bonds in LINC complexes play important roles in force transmission across the nuclear envelope. Other properties of LINC complexes, such as the helices preceding the SUN domain, the longer coiled-coils spanning the perinuclear space and higher-order organization may also function to transmit mechanical forces generated by the cytoskeleton across the nuclear envelope.

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Section: Other Factors That Influence Force Transmission Through Lincmentioning

confidence: 99%

Section: Other Factors That Influence Force Transmission Through Lincmentioning

confidence: 99%

Section: Other Factors That Influence Force Transmission Through Lincmentioning

confidence: 99%

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SUN/KASH interactions facilitate force transmission across the nuclear envelope

Hao

Starr

2019

Nucleus

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“…In budding yeast, the combined action of Mps2 and Csm4 is needed to carry out the function of the canonical KASH protein at the t-LINC. On the basis of the current understanding of the oligomerization state of SUN and KASH proteins (Sosa et al, 2012;Wang et al, 2012;Jahed et al, 2018), we propose that the yeast t-LINC is a nonamer ( Fig 5E). In Arabidopsis, WIP and WIT proteins are located at the ONM and appear to interact with each other to function as a KASH protein (Meier, 2016), which is analogous to Mps2 and Csm4.…”

Section: Reconstituted T-linc Can Tether Telomeresmentioning

confidence: 76%

Mps2 links Csm4 and Mps3 to form a telomere-associated LINC complex in budding yeast

Fan

Jin

Koch

et al. 2020

Preprint

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The linker of the nucleoskeleton and cytoskeleton (LINC) protein complex is composed of a pair of transmembrane proteins: the KASH-domain protein localized to the outer nuclear membrane and the SUN-domain protein to the inner nuclear membrane. In budding yeast, the sole SUN-domain protein, Mps3, is thought to pair with either Csm4 or Mps2, two KASH-like proteins, to form two separate LINC complexes. Here we show that Mps2 mediates the interaction between Csm4 and Mps3 to form a heterotrimeric telomere-associated LINC (t-LINC) in budding yeast meiosis. Mps2 binds to Csm4 and Mps3, and all three are localized to the telomere. Telomeric localization of Csm4 depends on both Mps2 and Mps3; in contrast,Mps2's localization depends on Mps3 but not Csm4. Mps2-mediated t-LINC regulates telomere movement and meiotic recombination. By ectopically expressing CSM4 in vegetative yeast cells, we reconstitute the heterotrimeric t-LINC and demonstrate its ability to tether telomeres. Our findings therefore reveal the heterotrimeric composition of t-LINC in budding yeast and have implications for understanding LINC variant formation.

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“…Thus, the canonical model of the LINC complex is of individual linear structures that provide independent nucleocytoskeletal couplings. Whilst it has been proposed that branching or higher-order assembly between LINC complexes may be advantageous in distributing large forces and achieving coordinated motions (Jahed et al, 2018;Lu et al, 2008;Sosa et al, 2013;Wang et al, 2012;Zhou et al, 2012), we have hitherto lacked structural evidence in favour of this hypothesis.Here, we provide crystallographic and biophysical evidence in support of the LINC complex forming a branched network rather than individual linear structures. We find that SUN-KASH complexes between SUN1 and Nesprin-4, KASH5 and Nesprin-1 are 6:6 structures that consist of constitutive back-to-back interactions between SUN trimers.…”

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confidence: 94%

A molecular mechanism for LINC complex branching by structurally diverse SUN-KASH 6:6 assemblies

Gurusaran

Davies

2020

Preprint

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The LINC complex mechanically couples cytoskeletal and nuclear components across the nuclear envelope to fulfil a myriad of cellular functions, including nuclear shape and positioning, hearing and meiotic chromosome movements. The canonical model of the LINC complex is of individual linear nucleocytoskeletal linkages provided by 3:3 interactions between SUN and KASH proteins. Here, we provide crystallographic and biophysical evidence that SUN-KASH is a constitutive 6:6 complex in which two SUN trimers interact back-to-back. A common SUN-KASH topology is achieved through structurally diverse 6:6 interaction mechanisms by distinct KASH proteins, including zinc-coordination by Nesprin-4. The SUN-KASH 6:6 complex is incompatible with the current model of a linear LINC complex and instead suggests the formation of a branched LINC complex network. In this model, SUN-KASH 6:6 complexes act as nodes for force distribution and integration between adjacent SUN and KASH molecules, enabling the coordinated transduction of large forces across the nuclear envelope. KeywordsLINC complex, nuclear envelope, SUN1, Nesprin-4, KASH5, Nesprin-1, X-ray crystallography, smallangle X-ray scattering, biophysics SUN proteins then traverse the approximately 50 nm peri-nuclear space and cross the inner nuclear membrane, enabling their N-termini to bind to nuclear contents, including reported interactions with the nuclear lamina (Crisp et al., 2006; Haque et al., 2006; Haque et al., 2010), chromatin (Chi et al., 2007) and the telomeric ends of meiotic chromosomes (Shibuya et al., 2014). Similarly, KASH domain proteins cross the outer nuclear membrane and have large cytoplasmic extensions to enable their Ntermini to bind to the cytoskeleton (Spindler et al., 2019; Starr and Fridolfsson, 2010). Thus, the LINC complex axis is established by a peri-nuclear SUN-KASH core interaction and mechanically couples the cytoskeleton and nuclear contents (Figure 1a). In mammals, there are five SUN proteins, of which SUN1 and SUN2 are widely expressed and perform partially redundant functions (Lei et al., 2009; Zhang et al., 2009). There are similarly multiple KASH proteins, four of which are Nesprins (Nuclear Envelope Spectrin Repeat proteins). Nesprin-1 and Nesprin-2 are widely expressed, perform overlapping functions and contain large cytoplasmic spectrin-repeat domains with N-termini that bind to actin (Banerjee et al., 2014; Starr and Fridolfsson, 2010). Nesprin-3 shares a similar KASH domain but its cytoplasmic region binds to plectin, mediating interactions with intermediate filaments (Ketema and Sonnenberg, 2011). The two most divergent KASH proteins, Nesprin-4 and KASH5, exhibit substantial sequence diversity within their KASH domains (Figure 1b). Nesprin-4 functions in the outer hair cells of the inner ear and is essential for hearing (Horn et al., 2013a). Its N-terminus interacts with kinesin, which mediates microtubule binding and plus-end directed movements that achieve the basal positioning of nuclei (Horn et al., 2013a; Roux et al., 2009). KA...

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Molecular Insights into the Mechanisms of SUN1 Oligomerization in the Nuclear Envelope

Cited by 40 publications

References 65 publications

SUN/KASH interactions facilitate force transmission across the nuclear envelope

SUN/KASH interactions facilitate force transmission across the nuclear envelope

Mps2 links Csm4 and Mps3 to form a telomere-associated LINC complex in budding yeast

A molecular mechanism for LINC complex branching by structurally diverse SUN-KASH 6:6 assemblies

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