Affinage

SYNE2

Nesprin-2 · UniProt Q8WXH0

Length
6885 aa
Mass
796.4 kDa
Annotated
2026-06-10
65 papers in source corpus 36 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Nesprin-2 (SYNE2) is a giant multi-isoform scaffold of the nuclear envelope that physically couples the actin cytoskeleton to the nucleus, forming the core of the LINC complex (PMID:12118075, PMID:15843432). Its N-terminal calponin-homology actin-binding domain (ABD) binds F-actin and additionally engages the actin-bundling proteins FHOD1 and fascin, while its C-terminal KASH/transmembrane region targets it to the outer nuclear membrane (PMID:12118075, PMID:30141036). The KASH-bearing C-terminus binds SUN1/SUN2 via a conserved luminal PPPX motif, and these SUN proteins, together with lamin A/C and emerin, complete the nucleus-spanning LINC bridge; SUN1, lamin A/C and emerin are each required for proper Nesprin-2 envelope localization, and Nesprin-2 reciprocally organizes emerin (PMID:16079285, PMID:15843432, PMID:15671068). Through this linkage Nesprin-2 transmits actomyosin-derived pulling forces to the nucleus during confined and polarized migration, behaving as an ABD-dependent, lamina-independent force coupler whose ABD forms a catch-bond with actin and whose spectrin repeats reversibly unfold to buffer piconewton-scale forces (PMID:32419336, PMID:41576090, PMID:40340251). Genetically, Syne-2 acts redundantly with Syne-1 to anchor myonuclei and maintain cardiac function, and it drives interkinetic and post-mitotic nuclear migration in retina and brain by recruiting the dynein/kinesin adaptor BicD2 through a LEWD motif-adjacent spectrin-repeat site, activating processive dynein/dynactin motility while permitting simultaneous kinesin-1 binding (PMID:17267447, PMID:21177258, PMID:24586179, PMID:32619477, PMID:36930595, PMID:41770881). Beyond the envelope, smaller KASH-less isoforms scaffold ERK1/2 at PML nuclear bodies to control proliferation and the DNA damage response, and tether α-/β-catenin at cell-cell junctions to regulate Wnt/TCF-LEF transcription (PMID:19861416, PMID:25744025, PMID:20801886, PMID:27321956). Nesprin-2 further contributes to ciliogenesis via meckelin and pericentrin, to faithful chromosome segregation through an SMC-like domain that binds condensin SMC2/SMC4, and to intrinsic apoptosis, where it relocates to mitochondria and promotes Bax/Bak activation and cytochrome c release via BH3-like motifs (PMID:19596800, PMID:30054381, PMID:29445399, PMID:38225256, PMID:39402980, PMID:40461467).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2002 High

    Established that Nesprin-2 is a bona fide physical link between the actin cytoskeleton and the nucleus, defining its bipartite architecture.

    Evidence In vitro F-actin binding, GFP-fusion colocalization and domain deletion mapping a C-terminal NE-targeting transmembrane domain

    PMID:12118075

    Open questions at the time
    • Did not identify the perinuclear partners anchoring the C-terminus
    • No force-transmission function demonstrated
  2. 2005 High

    Defined the molecular composition of the nuclear-envelope LINC bridge by showing Nesprin-2 binds SUN1, lamin A/C and emerin, with these partners mutually required for correct localization.

    Evidence Co-IP, pulldown, lamin A/C-null fibroblasts, dominant-negative SUN1/lamin mutants, siRNA and immunogold EM

    PMID:15671068 PMID:15843432 PMID:16079285

    Open questions at the time
    • Stoichiometry and structure of the SUN-KASH interface not resolved
    • Functional consequence of the bridge for force transfer untested
  3. 2007 High

    Demonstrated in vivo physiological essentiality of the KASH-anchored complex by showing Syne-1/Syne-2 redundantly anchor myonuclei in skeletal muscle.

    Evidence Single and double KASH-domain knockout mice with histology and innervation analysis

    PMID:17267447

    Open questions at the time
    • Did not separate force-anchoring from signaling roles
    • Mechanism of myonuclear positioning not dissected
  4. 2008 High

    Showed the actin-binding domain itself is required in vivo for nuclear shape, size and emerin organization, linking cytoskeletal engagement to envelope integrity.

    Evidence Nesprin-2ΔABD knockout mice with immunofluorescence and confocal microscopy

    PMID:18477613

    Open questions at the time
    • Did not quantify forces transmitted through the ABD
    • Did not address isoform-specific contributions
  5. 2009 High

    Expanded Nesprin-2 function beyond the envelope, implicating it in ciliogenesis and revealing KASH-less isoforms as nuclear ERK1/2 scaffolds controlling proliferation.

    Evidence Co-IP with meckelin, siRNA, RhoA activation and patient cells; GST pulldown, dominant-negative fragments and ERK reporter assays at PML NBs

    PMID:19596800 PMID:19861416

    Open questions at the time
    • How meckelin and ERK functions relate to LINC architecture unclear
    • Isoform boundaries for each role not mapped
  6. 2010 High

    Connected the LINC complex to microtubule motors and identified its role in directed nuclear migration in retina, plus a junctional Wnt-signaling function via catenins.

    Evidence Co-IP with dynein/dynactin and kinesin, retina-specific KO mice with ERG; α/β-catenin Co-IP, siRNA and TCF/LEF reporter assays

    PMID:20801886 PMID:21177258

    Open questions at the time
    • Direct motor-adaptor bridging molecule not yet identified
    • Did not establish whether catenin scaffolding occurs at the NE or junctions
  7. 2012 Medium

    Linked Nesprin-2 Giant to chromatin organization and tissue-level migration, indicating a genome-organizing role.

    Evidence ChIP-Seq of heterochromatin/centromeres plus knockout mouse wound-healing and migration assays

    PMID:22198684

    Open questions at the time
    • Chromatin association not mechanistically characterized
    • Whether DNA contact is direct or via partners unknown
  8. 2013 Medium

    Mapped the lamin A/Nesprin-2 binding interface at residue resolution and showed laminopathy mutations modulate LINC assembly.

    Evidence GST pulldown with truncation/point mutants, Co-IP and patient fibroblast immunofluorescence

    PMID:23977161

    Open questions at the time
    • No crystal/cryo-EM structure of the interface
    • Functional impact on force transmission not quantified
  9. 2014 High

    Demonstrated tissue-specific physiological requirement in heart and endothelium, tying Nesprin loss to mechanoresponsive gene expression and vascular function.

    Evidence Cardiomyocyte double-KO mice with echocardiography and expression profiling; endothelial RNAi with migration and angiogenesis assays

    PMID:24586179 PMID:24931616

    Open questions at the time
    • Mechanistic chain from nuclear coupling to altered transcription not resolved
    • Endothelial work limited to single-lab siRNA
  10. 2015 Medium

    Established that nuclear ERK1/2 scaffolding by Nesprin-2 is required for the DNA damage response and that Ca2+/Calmodulin-dependent nuclear transport of factors depends on Nesprin-2.

    Evidence siRNA, ATM/Chk2 phosphorylation immunoblots, comet assay; shRNA, ABD-Calmodulin Co-IP and calcium imaging

    PMID:25744025 PMID:26645154

    Open questions at the time
    • Direct molecular link between ERK scaffolding and ATM recruitment undefined
    • Mechanism of RAN-independent transport not fully resolved
  11. 2016 Medium

    Resolved the junctional pool of Nesprin-2, showing KASH-less variants sequester β-catenin at cell-cell contacts independently of the nuclear envelope.

    Evidence siRNA, calcium switch, Co-IP and β-catenin reporter assays

    PMID:27321956

    Open questions at the time
    • Variant-specific targeting determinants to junctions unknown
    • Relationship to envelope catenin pool unresolved
  12. 2017 Medium

    Uncovered a mitotic role via an SMC-like domain binding condensin, implicating Nesprin-2 in chromosome segregation fidelity.

    Evidence Co-IP, GST pulldown, cell-cycle immunofluorescence and siRNA with anaphase bridge quantification

    PMID:29445399

    Open questions at the time
    • How an envelope protein contacts condensin during open mitosis unclear
    • Direct vs. indirect SMC2/SMC4 binding untested structurally
  13. 2018 Medium

    Defined the cytoskeletal actin-bundling partners (FHOD1, fascin) and the ciliogenesis partner pericentrin, broadening the actin-side interactome.

    Evidence Actin co-sedimentation and GST pulldown; interaction screen, Co-IP, CRISPR KO and ciliogenesis assays

    PMID:30054381 PMID:30141036

    Open questions at the time
    • Quantitative contribution of FHOD1/fascin to nuclear coupling not measured
    • Pcnt-Syne2 complex structure unknown
  14. 2020 High

    Provided direct biophysical evidence that Nesprin-2 transmits actomyosin pulling forces to the nucleus and identified BicD2 as the LEWD-recruited motor adaptor sufficient for neuronal migration.

    Evidence CRISPR endogenous tagging, laser ablation mechanics, drug perturbation; in utero electroporation, LEWD mutagenesis and Co-IP

    PMID:32419336 PMID:32619477

    Open questions at the time
    • Force magnitudes at single-molecule level not yet measured (resolved later)
    • How ABD- vs motor-driven modes are selected per cell type unclear
  15. 2021 Medium

    Showed Nesprin-2 is required for mechanically induced differentiation and developmental cytoskeletal organization across species.

    Evidence Dermal fibroblast siRNA with cyclic stretch and Western blot; zebrafish syne2b CRISPR mutants with live imaging and F-actin staining

    PMID:34222245 PMID:34558192

    Open questions at the time
    • Mechanotransduction signaling steps downstream of Nesprin-2 undefined
    • Single-lab fibroblast dataset
  16. 2023 High

    Revealed competitive regulation of nuclear migration through mutually exclusive RanBP2-BicD2 and Nesprin-2-BicD2 interactions that partition migration stages.

    Evidence In vitro competitive binding plus in utero electroporation with BICD2 disease mutants

    PMID:36930595

    Open questions at the time
    • Switch mechanism controlling competition in vivo not defined
    • Structural basis of competition pending
  17. 2024 High

    Defined sarcomeric isoform partners (telethonin, FHL-2) and disease-modulated interactions, and established Nesprin-2's pro-apoptotic and cardiac-electrophysiological roles.

    Evidence Y2H/pulldown/Co-IP and cardiomyocyte localization; siRNA apoptosis assays and endogenous-tag live imaging of mitochondrial relocation; CRISPR variant mapping and iPSC-CM functional assays

    PMID:38225256 PMID:38569934 PMID:39355904 PMID:39402980

    Open questions at the time
    • Mechanism coupling envelope-to-mitochondria relocation to apoptosis incomplete (addressed 2025)
    • Causal variant work limited to single lab
  18. 2025 High

    Provided the biophysical and structural mechanism: spectrin-repeat force buffering, ABD catch-bond behavior, BH3-mediated Bcl-2 family engagement, and FHOD-activated actin bundling.

    Evidence Magnetic tweezers and MD; ABD catch-bond mutagenesis with imaging; AlphaFold/chimera BH3 binding and cytochrome c assays; FHOD bundling reconstitution and 3D acini (preprint)

    PMID:40340251 PMID:40461467 PMID:41576090 PMID:42011117

    Open questions at the time
    • Experimental high-resolution structures of full domains still lacking
    • BH3-like motif function based partly on modeling
  19. 2026 High

    Resolved the Nesprin-2/BicD2 motor-activation mechanism structurally and stoichiometrically and extended Nesprin-2 function to viral nuclear targeting.

    Evidence In vitro reconstitution of processive dynein motility with 1:2/2:2 stoichiometry and AlphaFold modeling; siRNA/SUN-domain mutant SV40 infection assays (preprint)

    PMID:41770881 PMID:41959248

    Open questions at the time
    • In vivo relevance of distinct stoichiometries untested
    • Viral targeting mechanism in preprint awaiting peer review

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single giant scaffold dynamically partitions among force transmission, motor-driven migration, chromatin/condensin contacts, signaling-scaffold and apoptotic roles within one cell remains unresolved.
  • No integrated model linking isoform expression to functional choice
  • Lack of experimental full-length structures
  • Regulatory switches governing envelope-to-mitochondria relocation undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0008092 cytoskeletal protein binding 4 GO:0098772 molecular function regulator activity 4 GO:0005198 structural molecule activity 3
Localization
GO:0005635 nuclear envelope 5 GO:0005856 cytoskeleton 3 GO:0000228 nuclear chromosome 2 GO:0005730 nucleolus 2 GO:0005739 mitochondrion 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-9609507 Protein localization 3 R-HSA-1640170 Cell Cycle 1 R-HSA-73894 DNA Repair 1
Partners
BICD2EMDFHOD1LMNASMC4SUN1SUN2TCAP
Complex memberships
LINC complex

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 NUANCE/Nesprin-2 contains an N-terminal alpha-actinin-like actin-binding domain (ABD) that binds F-actin in vitro and colocalizes with the actin cytoskeleton in vivo, and a C-terminal transmembrane domain responsible for targeting to the nuclear envelope, establishing it as a physical link between the microfilament system and the nucleus. In vitro F-actin binding assay, GFP-fusion colocalization, domain deletion analysis, subcellular fractionation Journal of cell science High 12118075
2005 Sun1 directly interacts with the conserved C-terminal luminal PPPX motif of Nesprin-2 (and Nesprin-1) and is required for proper nuclear envelope localization of Nesprin-2; dominant-negative Sun1 and Sun1 knockdown both cause Nesprin-2 mislocalization. Co-immunoprecipitation, dominant-negative mutant expression, siRNA knockdown, immunofluorescence Journal of cell science High 16079285
2005 Nesprin-2 binds directly to emerin and to the C-terminal common region of lamin A/C; lamin A/C is required for nuclear envelope localization of Nesprin-2, and Nesprin-2 in turn is required for proper nuclear envelope localization of emerin, indicating a scaffolding function. Biochemical pulldown, lamin A/C knockout fibroblasts, dominant-negative lamin B mutant, immunofluorescence Molecular biology of the cell High 15843432
2005 Smaller isoforms of nesprin-2 colocalize with and bind lamin A and emerin at the inner nuclear envelope; in SW-13 cells lacking lamin A/C, nesprin-2 epitopes and emerin are mislocalized to the ER, demonstrating lamin A/C-dependent NE retention. Larger isoforms localize to heterochromatin and the outer NE, and isoforms relocalize to the sarcomere during muscle differentiation. Co-immunoprecipitation, immunofluorescence in lamin A/C-null cells, immunogold electron microscopy, confocal microscopy in C2C12 differentiation Journal of cell science High 15671068
2007 Deletion of the KASH domain of Syne-2 in mice does not alone cause lethality, but combined Syne-1/Syne-2 KASH double-knockout causes neonatal death from respiratory failure, demonstrating that Syne-1 and Syne-2 together are essential for anchoring myonuclei in skeletal muscle. Conditional KASH-domain knockout mice (single and double), histology, motor innervation analysis Development (Cambridge, England) High 17267447
2008 Loss of the actin-binding domain of Nesprin-2 Giant in mice causes nuclear shape defects, increased nuclear size, mislocalization/aggregation of emerin at the nuclear envelope, and altered nuclear envelope architecture, establishing the ABD as required for nuclear envelope integrity and emerin organization. Actin-binding domain knockout mice (Nesprin-2ΔABD), immunofluorescence, confocal microscopy Journal of cell science High 18477613
2009 Nesprin-2 isoforms interact with meckelin (MKS3) and colocalize at filopodia prior to ciliogenesis; loss of nesprin-2 by siRNA impairs centrosome migration and ciliogenesis, and loss of meckelin causes aberrant actin remodeling, mislocalization of nesprin-2 to stress fibers, and RhoA activation. Co-immunoprecipitation, siRNA knockdown, immunofluorescence, RhoA activation assay, patient cell line analysis Journal of cell science High 19596800
2009 Nuclear nesprin-2 isoforms lacking the KASH domain act as scaffold proteins that tether active ERK1/2 at promyelocytic leukemia protein nuclear bodies (PML NBs); disruption of nesprin-2 by siRNA or dominant-negative fragments augments ERK1/2 nuclear signaling (increased SP1 activity, ELK1 phosphorylation) and increases smooth muscle cell proliferation. GST pulldown, immunoprecipitation, immunofluorescence, siRNA knockdown, dominant-negative overexpression, reporter assays The Journal of biological chemistry High 19861416
2010 Nesprin-2 forms complexes with SUN1 or SUN2 at the nuclear envelope and connects the nucleus with dynein/dynactin and kinesin motors during interkinetic nuclear migration and photoreceptor cell migration in the mouse retina; deletion of Syne-2 or double deletion of Sun1/Sun2 causes severe ONL thinning, photoreceptor nuclear mislocalization, and electrophysiological defects. Co-immunoprecipitation, retinal-specific knockout mice, ERG, confocal immunofluorescence Human molecular genetics High 21177258
2010 Nesprin-2 giant C-terminus interacts with α-N/E-catenins; nesprin-2 forms complexes containing α-catenin, β-catenin, and emerin at the nuclear envelope; depletion of nesprin-2 reduces nuclear active β-catenin and TCF/LEF-dependent transcription, identifying nesprin-2 as a positive regulator of Wnt signaling. Co-immunoprecipitation, siRNA knockdown, TCF/LEF luciferase reporter assay, immunofluorescence The Journal of biological chemistry High 20801886
2012 Nesprin-2 Giant associates with heterochromatic and centromeric DNA as detected by ChIP-Seq; loss of Nesprin-2 Giant in vivo delays wound healing, alters transcription factor localization, disrupts perinuclear actin cytoskeleton, slows keratinocyte migration, and enhances focal adhesion formation. ChIP-Seq, knockout mouse wound healing assay, immunofluorescence, migration assay, focal adhesion analysis Nucleus (Austin, Tex.) Medium 22198684
2013 The interaction between lamin A and Nesprin-2 maps to amino acids 403-425 in lamin A and aa 6146-6347 in Nesprin-2; laminopathic mutations in lamin A (R401C, G411D, G413C, V415I, R419C, L421P, R427G, Q432X) modulate this interaction and alter LINC complex assembly and chromosomal/transcription factor organization. GST pulldown with truncation and point mutants, co-immunoprecipitation, immunofluorescence in patient fibroblasts PloS one Medium 23977161
2014 Combined ablation of nesprin-1 and nesprin-2 (but not either alone) in cardiomyocytes causes early-onset cardiomyopathy with altered nuclear positioning, shape, and chromatin positioning, and impairs biomechanically responsive gene expression programs. Cardiomyocyte-specific double knockout mice, echocardiography, immunofluorescence, gene expression profiling PLoS genetics High 24586179
2014 Nesprin-1 and nesprin-2 depletion in endothelial cells increases cell spread area, stress fiber assembly, F-actin levels, nuclear area, reduces emerin localization at the NE, and impairs cell migration and in vitro angiogenic loop formation. RNAi knockdown, immunofluorescence, scratch wound migration assay, in vitro angiogenesis assay Cytoskeleton (Hoboken, N.J.) Medium 24931616
2015 Nesprin-2 scaffolds ERK1/2 at PML NBs at sites of DNA damage; nesprin-2 depletion removes ATM from DNA lesions, ablates Chk2 activation, and induces genomic instability; lamin A/C depletion does not abolish ATM signaling, demonstrating that nesprin-2/ERK signaling fidelity (not merely compartmentalization) is essential for the DNA damage response. siRNA knockdown, immunofluorescence, Chk2/ATM phosphorylation immunoblot, comet assay Cell death and differentiation Medium 25744025
2016 N-terminal nesprin-2 variants (lacking KASH domain) localize to cell-cell junctions where they interact with β-catenin; siRNA depletion of these variants causes loss of β-catenin from cell-cell junctions, nuclear accumulation of active β-catenin, and augmented β-catenin transcriptional activity, independently of the nuclear envelope. siRNA knockdown, immunofluorescence, calcium switch assay, co-immunoprecipitation, β-catenin reporter assay Experimental cell research Medium 27321956
2017 Nesprin-2 contains an SMC-like domain (aa 1436-1766) that interacts with the condensin core subunits SMC2 and SMC4 throughout the cell cycle (particularly in S phase and mitosis); nesprin-2 knockdown results in significantly higher numbers of chromatin bridges in anaphase. Co-immunoprecipitation, GST pulldown, immunofluorescence across cell cycle, siRNA knockdown with mitotic bridge quantification International journal of cell biology Medium 29445399
2018 Nesprin-2G interacts with actin filaments via its paired calponin homology domains and additionally binds the actin-bundling proteins FHOD1 and fascin; these interactions were measured by actin co-sedimentation assay and GST pulldown. Actin co-sedimentation assay, GST pulldown Methods in molecular biology Medium 30141036
2018 Pericentrin (Pcnt) is an interaction partner of Syne-2/Nesprin-2 in photoreceptors; CRISPR/Cas9 knockout of Syne-2 in cell culture causes overexpression and mislocalization of Pcnt and ciliogenesis defects, indicating the Pcnt-Syne-2 complex is required for ciliogenesis and outer segment formation. Protein interaction screen, Co-IP validation, CRISPR/Cas9 KO, immunofluorescence, in vivo shRNA knockdown of Pcnt Journal of cell science Medium 30054381
2020 During confined cell migration, nesprin-2 giant accumulates at the front of the nucleus in a manner dependent on its actin-binding domain but independent of the nuclear lamina; actin organizes in a barrel structure around the nucleus, and actomyosin-dependent pulling force from the cell front is dampened when nesprins are reduced, demonstrating nesprin-2 transmits actin-based pulling forces to the nucleus. CRISPR/Cas9 fluorescent tagging, FRAP, two-photon laser ablation, cytoskeleton drug treatment, artificial domain constructs, immunofluorescence EMBO reports High 32419336
2020 Nesprin-2 recruits the dynein/kinesin adaptor BicD2 to the nuclear envelope via its LEWD sequence motif; a ~100 kDa mini-Nesprin-2 (binding dynein and kinesin but lacking the ABD) is sufficient for neuronal migration in vivo; kinesin-1 opposes dynein-driven forward nuclear movement; the actin-binding domain of nesprin-2 is dispensable for neuronal migration. In utero electroporation (rat brain), dominant-negative constructs, LEWD motif mutagenesis, Co-immunoprecipitation, live imaging Current biology : CB High 32619477
2021 Silencing Nesprin-2 in dermal fibroblasts blocks mechanical-stretch-induced myofibroblast differentiation, reducing expression of lamin A/C, alpha-smooth muscle actin, TGF-β1, and collagen type I, establishing Nesprin-2 as a required mechanotransducer in this differentiation pathway. siRNA knockdown, cyclic mechanical stretch device, Western blot, immunofluorescence International wound journal Medium 34558192
2021 Zebrafish syne2b/nesprin-2 mutants (KASH domain truncation by CRISPR/Cas9) exhibit delayed epiboly, aberrant F-actin clustering at cell contacts, abnormal cell shape changes, disintegration of the epithelial blastoderm, and defective yolk syncytial nuclear migration, demonstrating Syne2b is required for cytoskeletal organization and epithelial integrity during epiboly. CRISPR/Cas9 knockout zebrafish, live imaging, F-actin staining, confocal microscopy Frontiers in cell and developmental biology Medium 34222245
2023 Nesprin-2 and RanBP2 compete for binding to BicD2 in vitro; mutually exclusive RanBP2-BicD2 vs. Nesprin-2-BicD2 interactions at the NE successively control interkinetic nuclear migration in radial glial progenitors (via RanBP2-BicD2) and post-mitotic neuronal migration (via Nesprin-2-BicD2); BICD2 disease mutations differentially affect these interactions. In vitro competitive binding assays, in utero electroporation in rat brain, biochemical binding assays with BICD2 mutants PLoS genetics High 36930595
2024 Specific nesprin-2 isoforms localize to the Z-disc and I-band of the sarcomere in cardiac muscle; nesprin-2 binds telethonin and FHL-2 (confirmed by GST pulldown and Co-IP); nesprin-2/telethonin binding is phosphorylation-dependent; EDMD/DCM/HCM disease mutations in nesprin-2, telethonin, or FHL-2 impair these interactions. Yeast two-hybrid screen, GST pulldown, co-immunoprecipitation, GFP-fusion localization in neonatal cardiomyocytes, mutant binding analysis The Journal of biological chemistry High 38569934
2024 Depletion of nesprin-2 inhibits the intrinsic apoptotic pathway: Bax and Bak activation, cytochrome c release, and Bak N-terminus exposure are all reduced; this survival effect is Bcl-xL-dependent; nesprin-2 regulates mitochondrial translocation/retrotranslocation of Bcl-2 family proteins. siRNA knockdown, Bax/Bak activation assay, cytochrome c release assay, flow cytometry, immunofluorescence Cell death discovery Medium 38225256
2024 Upon apoptosis induction, endogenous GFP-tagged nesprin-2 giant redistributes from the nuclear envelope to the vicinity of mitochondria; this redistribution is associated with reduced mitochondrial membrane potential and outer membrane permeabilization, and precedes morphological features of apoptosis. CRISPR GFP-tagging, live-cell time-lapse imaging, mitochondrial membrane potential (JC-1 dye), mitochondrial outer membrane permeabilization assay Nucleus (Austin, Tex.) Medium 39402980
2024 The SYNE2 risk variant rs1152591 reduces promoter/enhancer activity and specifically lowers expression of the short SYNE2α1 isoform in cardiomyocytes; SYNE2α1 overexpression or SYNE2 knockdown increases nuclear area and decreases nuclear stiffness; SYNE2α1 overexpression shortens action potential duration and accelerates calcium reuptake, while SYNE2 knockdown decreases conduction velocity. Reporter gene transfection, CRISPR-Cas9 editing, iPSC-derived cardiomyocyte KD/OE, atomic force microscopy, optical mapping, Fura-2 calcium imaging, RNAseq Circulation. Genomic and precision medicine Medium 39355904
2025 Nesprin-2 giant spectrin repeat domains undergo reversible mechanical unfolding and refolding at pN-scale forces (distinct transition rates per SR domain), enabling giant nesprin-2 to act as a molecular force absorber that maintains nucleoskeleton-cytoskeleton linkage forces within a few pN over displacement spans exceeding 1 µm; pN-level forces modulate nesprin-protein interactions via domain folding/unfolding dynamics. Magnetic tweezers single-molecule manipulation, molecular dynamics simulations, AlphaFold structural predictions Proceedings of the National Academy of Sciences High 41576090
2025 During confined cell migration, SUN2 (but not SUN1) shows the same frontal accumulation as nesprin-2; the nesprin-2 actin-binding domain acts as a catch-bond with actin (binding strengthened by pulling force), and a specific ABD point mutation that abrogates catch-bond behavior reduces frontal nesprin-2 accumulation, as predicted by a physical model. Quantitative fluorescence imaging of endogenous-tagged proteins, chimeric mininesprin-2 constructs with point mutations, physical modeling Biophysical journal Medium 40340251
2025 Nesprin-2 contains two BH3-like motifs near its N- and C-termini that adopt amphipathic α-helix structures predicted to dock onto Bax and anti-apoptotic Bcl-2 proteins; chimeric tBid with the C-terminal Nes2 BH3-like domain binds Bax in cells; BH3-like motif-containing fragments bind multidomain Bcl-2 family proteins and promote cytochrome c release. Molecular modeling (AlphaFold), chimeric protein construction and Co-IP, cytochrome c release assay, in vitro binding Cell death discovery Medium 40461467
2025 Nesprin-2 interaction with FHOD formins activates FHOD actin-bundling activity; FHOD-associated LINC complexes enhance mechanical resistance of nuclear-engaged actin cables in polarizing fibroblasts and sarcomeres in developing cardiomyocytes; depletion of nesprin-2G, SUN proteins, or FHOD1 disrupts nuclear positioning and lumen formation in 3D breast acini. Biochemical reconstitution of FHOD actin bundling, in vitro binding assays, cell depletion (LINC component knockdown), 3D acini culture bioRxivpreprint Medium
2025 A structural model of the minimal Nesprin-2/BicD2 complex shows spectrin repeats of Nesprin-2 forming an α-helical bundle with BicD2's cargo-binding domain; the BicD2-binding site is spatially separated from the LEWD kinesin-1 recruitment site, allowing simultaneous motor binding; minimal Nesprin-2 fragment activates processive dynein/dynactin/BicD2 motility in vitro without additional components. AlphaFold structural prediction, mutagenesis, binding assays, single-molecule biophysical studies, in vitro reconstitution of dynein motility bioRxivpreprint Medium 40475460
2026 The minimal Nesprin-2/BicD2 complex can form 1:2 or 2:2 stoichiometries (one or two Nesprin-2 per BicD2 dimer), both activating dynein/dynactin/BicD2 for processive motility at similar speed and run lengths; the BicD2 binding site is structurally distinct from Rab6/BicD2 and Nup358/BicD2 complexes; kinesin-1 and BicD2/dynein binding sites on Nesprin-2 do not overlap and can be simultaneously occupied. AlphaFold structural modeling, mutagenesis, binding assays, single-molecule biophysical studies, in vitro reconstitution Biochemistry High 41770881
2026 SV40 virus targets to nesprin-2 at the outer nuclear membrane; SUN1 (acting via its SUN domain despite being in the perinuclear space) cooperates with Nesprin-2 to recruit cytosolic SV40 to the nuclear membrane; after targeting, SV40 binds KPNA4 for nuclear pore-dependent nuclear entry, demonstrating Nesprin-2-SUN1 function in pathogen nuclear targeting. siRNA knockdown of Nesprin-2/SUN1, immunofluorescence, infection assays, Co-IP, SUN domain mutant analysis bioRxivpreprint Medium 41959248
2026 Farnesylated prelamin A (progerin and related variants) reduces diffusional mobility of nesprin-2 and SUN2 at the nuclear envelope in a farnesylation-dependent manner and inhibits their function in cell polarization; short C-terminal farnesylated tail fragments of prelamin A are sufficient to disrupt cell polarity, indicating farnesylation retention disrupts nesprin-2-SUN2 LINC complex-mediated actin force transmission to the nucleus. FRAP, cell polarity assays, expression of prelamin A variants and tail fragments, farnesylation inhibitor treatment, immunofluorescence Journal of cell science Medium 42011117
2015 Nesprin-2 depletion by shRNA causes abnormal nuclear localization of BRCA1 and NF-κB, and this nuclear transport occurs via a RAN-independent Ca²⁺/Calmodulin mechanism; the actin-binding domain of Nesprin-2 interacts with Calmodulin; loss of Nesprin-2 from the NE increases steady-state cytoplasmic Ca²⁺ concentration. shRNA knockdown, immunofluorescence, Co-immunoprecipitation (ABD-Calmodulin interaction), calcium imaging Nucleus (Austin, Tex.) Medium 26645154

Source papers

Stage 0 corpus · 65 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 The inner nuclear membrane protein Sun1 mediates the anchorage of Nesprin-2 to the nuclear envelope. Journal of cell science 346 16079285
2002 NUANCE, a giant protein connecting the nucleus and actin cytoskeleton. Journal of cell science 245 12118075
2007 Syne-1 and Syne-2 play crucial roles in myonuclear anchorage and motor neuron innervation. Development (Cambridge, England) 227 17267447
2005 Nesprin-2 is a multi-isomeric protein that binds lamin and emerin at the nuclear envelope and forms a subcellular network in skeletal muscle. Journal of cell science 222 15671068
2010 KASH protein Syne-2/Nesprin-2 and SUN proteins SUN1/2 mediate nuclear migration during mammalian retinal development. Human molecular genetics 144 21177258
2005 Lamin A/C-dependent localization of Nesprin-2, a giant scaffolder at the nuclear envelope. Molecular biology of the cell 143 15843432
2008 Nesprin-2 Giant (NUANCE) maintains nuclear envelope architecture and composition in skin. Journal of cell science 125 18477613
2015 Global loss of a nuclear lamina component, lamin A/C, and LINC complex components SUN1, SUN2, and nesprin-2 in breast cancer. Cancer medicine 122 26175118
2014 Targeted ablation of nesprin 1 and nesprin 2 from murine myocardium results in cardiomyopathy, altered nuclear morphology and inhibition of the biomechanical gene response. PLoS genetics 118 24586179
2009 Nesprin-2 interacts with meckelin and mediates ciliogenesis via remodelling of the actin cytoskeleton. Journal of cell science 116 19596800
2012 Multiple novel nesprin-1 and nesprin-2 variants act as versatile tissue-specific intracellular scaffolds. PloS one 101 22768332
2009 Nuance in the double-helix and its role in protein-DNA recognition. Current opinion in structural biology 82 19362815
2018 Colloidal aggregation: from screening nuisance to formulation nuance. Nano today 80 30250495
2010 Nesprin-2 interacts with {alpha}-catenin and regulates Wnt signaling at the nuclear envelope. The Journal of biological chemistry 63 20801886
2014 Nesprin-1 and nesprin-2 regulate endothelial cell shape and migration. Cytoskeleton (Hoboken, N.J.) 59 24931616
2007 Nesprin-2 giant safeguards nuclear envelope architecture in LMNA S143F progeria cells. Human molecular genetics 58 17881656
2012 The nuclear envelope protein Nesprin-2 has roles in cell proliferation and differentiation during wound healing. Nucleus (Austin, Tex.) 56 22198684
2020 Nesprin-2 accumulates at the front of the nucleus during confined cell migration. EMBO reports 54 32419336
2020 Nesprin-2 Recruitment of BicD2 to the Nuclear Envelope Controls Dynein/Kinesin-Mediated Neuronal Migration In Vivo. Current biology : CB 51 32619477
2009 Novel nuclear nesprin-2 variants tether active extracellular signal-regulated MAPK1 and MAPK2 at promyelocytic leukemia protein nuclear bodies and act to regulate smooth muscle cell proliferation. The Journal of biological chemistry 47 19861416
2015 Nesprin-2-dependent ERK1/2 compartmentalisation regulates the DNA damage response in vascular smooth muscle cell ageing. Cell death and differentiation 38 25744025
2013 Mutations in LMNA modulate the lamin A--Nesprin-2 interaction and cause LINC complex alterations. PloS one 35 23977161
2015 Nuance and behavioral cogency: How the Visible Burrow System inspired the Stress-Alternatives Model and conceptualization of the continuum of anxiety. Physiology & behavior 23 26066728
2016 EGFR and SYNE2 are associated with p21 expression and SYNE2 variants predict post-operative clinical outcomes in HBV-related hepatocellular carcinoma. Scientific reports 20 27502069
2022 Synonymous Variants: Necessary Nuance in Our Understanding of Cancer Drivers and Treatment Outcomes. Journal of the National Cancer Institute 19 35477782
2015 A Mutation in Syne2 Causes Early Retinal Defects in Photoreceptors, Secondary Neurons, and Müller Glia. Investigative ophthalmology & visual science 18 26066746
2024 LINC complex protein nesprin-2 has pro-apoptotic activity via Bcl-2 family proteins. Cell death discovery 16 38225256
2016 N-terminal nesprin-2 variants regulate β-catenin signalling. Experimental cell research 16 27321956
2023 Role of Nesprin-2 and RanBP2 in BICD2-associated brain developmental disorders. PLoS genetics 15 36930595
2016 Olfaction in context-sources of nuance in plant-pollinator communication. Current opinion in insect science 15 27436732
2015 Nesprin-2 mediated nuclear trafficking and its clinical implications. Nucleus (Austin, Tex.) 14 26645154
2007 NUA Activities at the Plant Nuclear Pore. Plant signaling & behavior 14 19704557
2021 Silencing of Nesprin-2 inhibits the differentiation of myofibroblasts from fibroblasts induced by mechanical stretch. International wound journal 10 34558192
2021 Biallelic SYNE2 Missense Mutations Leading to Nesprin-2 Giant Hypo-Expression Are Associated with Intellectual Disability and Autism. Genes 9 34573277
2018 Functional analyses of Pericentrin and Syne-2 interaction in ciliogenesis. Journal of cell science 9 30054381
2018 Depletion of Nesprin-2 is associated with an embryonic lethal phenotype in mice. Nucleus (Austin, Tex.) 8 30220251
2013 Nonsteroidal anti-inflammatory drug sulindac sulfide suppresses structural protein Nesprin-2 expression in colorectal cancer cells. Biochimica et biophysica acta 8 24080406
2022 NUA and ESD4 negatively regulate ABA signaling during seed germination. Stress biology 6 37676575
2019 Lack of a Retinal Phenotype in a Syne-2/Nesprin-2 Knockout Mouse Model. Cells 6 31614616
2018 Analysis of Nesprin-2 Interaction with Its Binding Partners and Actin. Methods in molecular biology (Clifton, N.J.) 6 30141036
2016 Neurological Nuance: Hodgkin lymphoma presenting with Guillain-BarrÉ syndrome. Muscle & nerve 6 27756115
2011 Nesprin-2 epsilon: a novel nesprin isoform expressed in human ovary and Ntera-2 cells. Biochemical and biophysical research communications 6 21820406
2016 Detection of Diverse and High Molecular Weight Nesprin-1 and Nesprin-2 Isoforms Using Western Blotting. Methods in molecular biology (Clifton, N.J.) 5 27147045
2024 Nesprin-2 is a novel scaffold protein for telethonin and FHL-2 in the cardiomyocyte sarcomere. The Journal of biological chemistry 4 38569934
2024 Apoptosis-induced translocation of nesprin-2 from the nuclear envelope to mitochondria is associated with mitochondrial dysfunction. Nucleus (Austin, Tex.) 4 39402980
2021 Syne2b/Nesprin-2 Is Required for Actin Organization and Epithelial Integrity During Epiboly Movement in Zebrafish. Frontiers in cell and developmental biology 4 34222245
2020 A novel SYNE2 mutation identified by whole exome sequencing in a Korean family with Emery-Dreifuss muscular dystrophy. Clinica chimica acta; international journal of clinical chemistry 4 32184094
2022 The thematic role of extracellular loop of VraG in activation of the membrane sensor GraS in a cystic fibrosis MRSA strain differs in nuance from the CA-MRSA strain JE2. PloS one 3 35737676
2018 Evaluation of Hansen et al.: Nuance Is Crucial in Comparisons of Noise. Cell systems 3 30359620
2017 No shortcuts: new findings reinforce why nuance is the rule in genetic autoinflammatory syndromes. Current opinion in rheumatology 3 28604422
2017 Acute myeloid leukemia with t(14;21) involving RUNX1 and SYNE2: A novel favorable-risk translocation? Cancer genetics 3 29025598
2017 Nesprin-2 Interacts with Condensin Component SMC2. International journal of cell biology 3 29445399
2006 Receptors as microprocessors: pharmacological nuance on metabotropic glutamate receptors 1alpha. Science's STKE : signal transduction knowledge environment 3 16818798
2025 The mechanism of nesprin-2 accumulation at the nucleus front during confined cell migration. Biophysical journal 2 40340251
2024 Common SYNE2 Genetic Variant Associated With Atrial Fibrillation Lowers Expression of Nesprin-2α1 With Downstream Effects on Nuclear and Electrophysiological Traits. Circulation. Genomic and precision medicine 2 39355904
2021 Emotional Nuance Enhances Verbatim Retention of Written Materials. Frontiers in psychology 2 34194352
2026 Force-dependent structural dynamics of the giant nesprin-2. Proceedings of the National Academy of Sciences of the United States of America 1 41576090
2025 Nesprin-2 contains BH3-like motifs that can promote cell death. Cell death discovery 1 40461467
2024 An Intronic Heterozygous SYNE2 Splice Site Mutation: A Rare Cause for Myalgia and hyperCKemia? Muscles (Basel, Switzerland) 1 40757551
2026 Cargo Recognition of Nesprin-2 by the Dynein Adapter Bicaudal D2 for a Nuclear Positioning Pathway That Is Important for Brain Development. Biochemistry 0 41770881
2026 SV40 exploits the Nesprin-2-SUN1-KPNA4 axis for stepwise targeting and entry into the host nucleus to promote infection. bioRxiv : the preprint server for biology 0 41959248
2026 Farnesylated prelamin A induces fibroblast polarity defects in premature aging disorders by inhibiting nesprin-2-SUN2 LINC complex function. Journal of cell science 0 42011117
2026 The 40% weight-reduction craze: market volatility, metabolic nuance, and the quest for sustainable health. Molecules and cells 0 42070752
2025 Cargo recognition of Nesprin-2 by the dynein adapter Bicaudal D2 for a nuclear positioning pathway that is important for neuronal migration. bioRxiv : the preprint server for biology 0 40475460
2016 [Nitrogen Removal and the Characteristics of Denitrification Bacteria Using NUA-DAS Ecofilter]. Huan jing ke xue= Huanjing kexue 0 29964476

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