A Disulfide Bond Is Required for the Transmission of Forces through SUN-KASH Complexes

Jahed, Zeinab; Shams, Hengameh; Mofrad, Mohammad R. K.

doi:10.1016/j.bpj.2015.06.057

Cited by 36 publications

(45 citation statements)

References 40 publications

(47 reference statements)

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“…Therefore, a diverse range of LINC complexes is possible, which may relate to their multiple functions. Here, I first review the structure of SUN proteins [39,40,41,42,43] recently revealed by crystallographic analyses, which is consistent with the established biochemical data. I then discuss the possible functions of the dynamic interactions between SUN and lamins.…”

Section: Introductionsupporting

confidence: 65%

Implications for Diverse Functions of the LINC Complexes Based on the Structure

Hieda

2017

Cells

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The linker of nucleoskeleton and cytoskeleton (LINC) complex is composed of the outer and inner nuclear membrane protein families Klarsicht, Anc-1, and Syne homology (KASH), and Sad1 and UNC-84 (SUN) homology domain proteins. Increasing evidence has pointed to diverse functions of the LINC complex, such as in nuclear migration, nuclear integrity, chromosome movement and pairing during meiosis, and mechanotransduction to the genome. In metazoan cells, the nuclear envelope possesses the nuclear lamina, which is a thin meshwork of intermediate filaments known as A-type and B-type lamins and lamin binding proteins. Both of lamins physically interact with the inner nuclear membrane spanning SUN proteins. The nuclear lamina has also been implicated in various functions, including maintenance of nuclear integrity, mechanotransduction, cellular signalling, and heterochromatin dynamics. Thus, it is clear that the LINC complex and nuclear lamins perform diverse but related functions. However, it is unknown whether the LINC complex–lamins interactions are involved in these diverse functions, and their regulation mechanism has thus far been elusive. Recent structural analysis suggested a dynamic nature of the LINC complex component, thus providing an explanation for LINC complex organization. This review, elaborating on the integration of crystallographic and biochemical data, helps to integrate this research to gain a better understanding of the diverse functions of the LINC complex.

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Section: Introductionsupporting

confidence: 65%

Implications for Diverse Functions of the LINC Complexes Based on the Structure

Hieda

2017

Cells

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“…4B). In agreement with the second proposed mechanism, our recent molecular dynamics simulations suggest that tensile cytoskeletal forces acting on KASH proteins can be directly transmitted to the luminal domain of SUN proteins without disrupting the SUN-KASH domain interactions, and thus might represent a possible mechanism underlying this extension (Jahed et al, 2015). However, cytoskeletal forces can only be transmitted The number of nucleoplasmic residues for each SUN-domain protein was extracted from uniprot.org.…”

Section: Roles Of Npcs and Linc Complexes In Nuclear Envelope Architementioning

confidence: 52%

“…Both structures reveal a trimeric SUN2 complex that simultaneously forms strong interactions with three KASH peptides in the PNS. The second, more complete structure (4DXS), also reveals a covalent disulfide interaction between two highly conserved cysteine residues of SUN2 and KASH2; this strongly stabilizes the interaction and is potentially crucial for the transmission of cytoskeletal forces to the nucleus (Jahed et al, 2015). LINC complexes interact directly with the nuclear envelope.…”

Section: Pnsmentioning

confidence: 99%

The LINC and NPC relationship – it's complicated!

Jahed

Soheilypour

Peyro

et al. 2016

Journal of Cell Science

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The genetic information of eukaryotic cells is enclosed within a double-layered nuclear envelope, which comprises an inner and outer nuclear membrane. Several transmembrane proteins locate to the nuclear envelope; however, only two integral protein complexes span the nuclear envelope and connect the inside of the nucleus to the cytoplasm. The nuclear pore complex (NPC) acts as a gateway for molecular exchange between the interior of the nucleus and the cytoplasm, whereas so-called LINC complexes physically link the nucleoskeleton and the cytoskeleton. In this Commentary, we will discuss recent studies that have established direct functional associations between these two complexes. The assembly of NPCs and their even distribution throughout the nuclear envelope is dependent on components of the LINC complex. Additionally, LINC complex formation is dependent on the successful localization of inner nuclear membrane components of LINC complexes and their transport through the NPC. Furthermore, the architecture of the nuclear envelope depends on both protein complexes. Finally, we will present recent evidence showing that LINC complexes can affect nucleo-cytoplasmic transport through the NPC, further highlighting the importance of understanding the associations of these essential complexes at the nuclear envelope.

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“…While the KASH2-SUN2 interaction was shown to require the cation loop, the disulfide bond appeared to be dispensable for binding 12 . However, molecular dynamics modeling recently demonstrated that this intermolecular disulfide bond was crucial for the stability of the KASH-SUN interaction as well as force transmission through the LINC complex 14 . The crystal structure of SUN2 in a complex with the KASH domain from SYNE-1/nesprin-1 was overall quite similar to the SUN2-KASH2 complex potentially explaining the conservation of the KASH domain 12 .…”

Section: Structural Insights Into Linc Complex Function and Regulationmentioning

confidence: 99%

LINCing Defective Nuclear-Cytoskeletal Coupling and DYT1 Dystonia

Saunders

Luxton

2016

Cel. Mol. Bioeng.

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Mechanical forces generated by nuclear-cytoskeletal coupling through the LINC (linker of nucleoskeleton and cytoskeleton) complex, an evolutionarily conserved molecular bridge in the nuclear envelope (NE), are critical for the execution of wholesale nuclear positioning events in migrating and dividing cells, chromosome dynamics during meiosis, and mechanotransduction. LINC complexes consist of outer (KASH (Klarsicht, ANC-1, and Syne homology)) and inner (SUN (Sad1, UNC-84)) nuclear membrane proteins. KASH proteins interact with the cytoskeleton in the cytoplasm and SUN proteins in the perinuclear space of the NE. In the nucleoplasm, SUN proteins interact with A-type nuclear lamins and chromatin-binding proteins. Recent structural insights into the KASH-SUN interaction have generated several questions regarding how LINC complex assembly and function might be regulated within the perinuclear space. Here we discuss potential LINC regulatory mechanisms and focus on the potential role of AAA+ (ATPases associated with various cellular activities) protein, torsinA, as a LINC complex regulator within the NE. We also examine how defects in LINC complex regulation by torsinA may contribute to the pathogenesis of the human neurological movement disorder, DYT1 dystonia.

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A Disulfide Bond Is Required for the Transmission of Forces through SUN-KASH Complexes

Cited by 36 publications

References 40 publications

Implications for Diverse Functions of the LINC Complexes Based on the Structure

Implications for Diverse Functions of the LINC Complexes Based on the Structure

The LINC and NPC relationship – it's complicated!

LINCing Defective Nuclear-Cytoskeletal Coupling and DYT1 Dystonia

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