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

Zhou, Zhaocai; Du, Xiulian; Cai, Zheng; Song, Xiaomin; Zhang, Hongtao; Mizuno, Takako; Suzuki, Emi; Yee, Marla; Berezov, Alan; Murali, Ramachandran; Wu, Shiaw‐Lin; Karger, Barry L.; Greene, Mark I.; Wang, Qiang

doi:10.1074/jbc.m111.304543

Cited by 123 publications

(153 citation statements)

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“…Disturbing the SUN domain BI-pocket by introduction of mutations, including A603E, Y703E, S641E and Y707A, impaired or abolished the GST-KASH binding activity, highlighting the importance of this docking site. Consistent with our previous work [12], mutation of the SUN domain surface residue G609D also disrupted the SUN-KASH assembly, which was most likely an indirect outcome caused by local conformational changes ( Figure 4A).…”

Section: Structure-based Mutational Analyses Of the Sun-kash Complex supporting

confidence: 78%

“…The affinity of the del AA'-SUN domain and the KASH domain could not be determined by Octet assay ( Figure 4A and 4B), suggesting that the formation of the intermolecular β-sheet between the AA'-loop and the KASH domain can greatly stabilize the anchoring of the PPPT motif by the BI-pocket. Of note, our previous work showed that deletion of the SUN domain stem region disrupted the homotrimer and completely abolished its KASH-binding ability [12]. This observation, together with the SUN-KASH structure, indicates that the sandwiching of the KASH domain by two protomers of the SUN domain homotrimer is critical for complex assembly.…”

Section: Structure-based Mutational Analyses Of the Sun-kash Complex mentioning

confidence: 89%

“…We previously reported the crystal structure of the SUN domain of human SUN2 as a homotrimer and mapped the essential domains required for SUN-KASH association [12]. We demonstrated that a synthesized peptide (termed the KASH peptide), corresponding to the conserved C-terminus of the human Nesprin 2G KASH domain, can bind to the SUN domain of human SUN2 and that disruption of the SUN domain homotrimer abolished the binding of the KASH peptide.…”

Section: Overall Structure Of the Sun-kash Complexmentioning

confidence: 99%

“…The luminal region of SUN2 contains two coiled-coil domains and a conserved SUN domain at the C-terminus [11] ( Figure 1A). According to our recent structural study of SUN2, the conserved SUN domain is essential and sufficient for KASH binding [12]. Endogenous SUN2 is localized to the NE and is partly dependent on lamin A, but not lamin C, for NE retention [13].…”

Section: Introductionmentioning

confidence: 99%

“…However, the assembly of the SUN-KASH core complex has not been fully defined at the atomic level, hindering further exploration of its functions. Based on our previous crystallographic study of the SUN domain [12], we performed structural, biochemical and cell-based studies of the SUN-KASH complex. We observed a 3:3 ratio in the hexameric SUN-KASH complex in which the SUN domain trimer binds three separate KASH peptides.…”

Section: Introductionmentioning

confidence: 99%

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Structural insights into SUN-KASH complexes across the nuclear envelope

et al. 2012

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Linker of the nucleoskeleton and the cytoskeleton (LINC) complexes are composed of SUN and KASH domaincontaining proteins and bridge the inner and outer membranes of the nuclear envelope. LINC complexes play critical roles in nuclear positioning, cell polarization and cellular stiffness. Previously, we reported the homotrimeric structure of human SUN2. We have now determined the crystal structure of the human SUN2-KASH complex. In the complex structure, the SUN domain homotrimer binds to three independent "hook"-like KASH peptides. The overall conformation of the SUN domain in the complex closely resembles the SUN domain in its apo state. A major conformational change involves the AA'-loop of KASH-bound SUN domain, which rearranges to form a mini β-sheet that interacts with the KASH peptide. The PPPT motif of the KASH domain fits tightly into a hydrophobic pocket on the homotrimeric interface of the SUN domain, which we termed the BI-pocket. Moreover, two adjacent protomers of the SUN domain homotrimer sandwich the KASH domain by hydrophobic interaction and hydrogen bonding. Mutations of these binding sites disrupt or reduce the association between the SUN and KASH domains in vitro. In addition, transfection of wild-type, but not mutant, SUN2 promotes cell migration in Ovcar-3 cells. These results provide a structural model of the LINC complex, which is essential for additional study of the physical and functional coupling between the cytoplasm and the nucleoplasm.

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Section: Structure-based Mutational Analyses Of the Sun-kash Complex supporting

confidence: 78%

Section: Structure-based Mutational Analyses Of the Sun-kash Complex mentioning

confidence: 89%

Section: Overall Structure Of the Sun-kash Complexmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structural insights into SUN-KASH complexes across the nuclear envelope

et al. 2012

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Dynamic regulation of LINC complex composition and function across tissues and contexts

King

2023

FEBS Letters

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The concept of mechanotransduction to the nucleus through a direct force transmission mechanism has fascinated cell biologists for decades. Central to such a mechanism is the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, which spans the nuclear envelope to couple the cytoplasmic cytoskeleton to the nuclear lamina. In reality, there is not one LINC complex identity, but instead a family of protein configurations of varied composition that exert both shared and unique functions. Regulated expression of LINC complex components, splice variants, and mechanoresponsive protein turnover mechanisms together shape the complement of LINC complex forms present in a given cell type. Disrupting specific gene(s) encoding LINC complex components therefore gives rise to a range of organismal defects. Moreover, evidence suggests that the mechanical environment remodels LINC complexes, providing a feedback mechanism by which cellular context influences the integration of the nucleus into the cytoskeleton. In particular, evidence for crosstalk between the nuclear and cytoplasmic intermediate filament networks communicated through the LINC complex represents an emerging theme in this active area of ongoing investigation.

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LINC Complexes and Their Role in Human Disease

Calvi

Burke

2015

Encyclopedia of Life Sciences

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In most metazoan cell types, the nucleus occupies a clearly defined region of the cytoplasm. For instance in epithelial cells, it is commonly positioned close to the basal membrane, whereas in skeletal muscle fibres, the majority of nuclei are uniformly distributed adjacent to the plasma membrane. A few muscle cell nuclei, however, cluster beneath the postsynaptic membrane. In certain cell types, the nucleus may be repositioned according to cell cycle phase or cell activity. Each of these situations requires that nuclei be physically coupled to the cytoskeleton. This is accomplished in large part by LINC (linker of the nucleoskeleton and cytoskeleton) complexes. These structures consist of inner nuclear membrane SUN (Sad1p‐UNC‐84)‐domain proteins that function as transluminal tethers for outer nuclear membrane KASH ‐domain proteins. Together, SUN–KASH pairs function as links in a molecular chain that couples cytoskeletal elements, including motor proteins, to nuclear components. In addition to having obligate roles in nuclear positioning and chromatin organisation, LINC complexes may also function in mechanotransduction. The fact that a number of human diseases have been associated with LINC complex defects indicates that in many cell types these represent essential structures at the interface between the nucleus and cytoplasm. Key Concepts The nuclear envelope forms the interface between the nucleus and cytoplasm. Its most prominent features are the inner and outer nuclear membranes (INM and ONM) separated by a narrow (∼50 nm) gap, the perinuclear space (PNS). SUN domain proteins of the INM function as transluminal tethers for KASH domain proteins in the ONM. The nucleoplasmic domain of SUN proteins provides binding sites for both chromatin proteins and components of the nuclear lamina. KASH domain proteins represent attachment sites at the nuclear envelope for a variety of cytoskeletal elements, including motor proteins. SUN–KASH pairs, which span both nuclear membranes, are known as LINC (linker of the nucleoskeleton and cytoskeleton) complexes and mechanically couple nuclear structures to the cytoskeleton. LINC complexes have essential roles in nuclear migration and positioning in multiple cell types. During meiosis, LINC complexes have an essential role in telomere‐led chromosome movement, a process that facilitates homologous chromosome pairing and synapsis. LINC complexes are thought to mediate the transmission of mechanical signals to the nucleus: mechanotransduction.

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

Cited by 123 publications

References 58 publications

Structural insights into SUN-KASH complexes across the nuclear envelope

Structural insights into SUN-KASH complexes across the nuclear envelope

Dynamic regulation of LINC complex composition and function across tissues and contexts

LINC Complexes and Their Role in Human Disease

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