Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt.
Gene Ontology annotation based on curation of immunofluorescence data
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara.
Combined Automated Annotation using Multiple IEA Methods.
LEM2 is a novel MAN1-related inner nuclear membrane protein associated with A-type lamins.
The inner nuclear membrane protein Lem2 is critical for normal nuclear envelope morphology.
Loss of function of the nuclear envelope protein LEMD2 causes DNA damage-dependent cardiomyopathy.
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Knockin mice carrying the human LEMD2 c.T38>G (p.L13R) LEM-domain mutation phenocopy human disease, developing severe dilated cardiomyopathy and cardiac fibrosis; cardiomyocyte-specific Lemd2 KO mice die shortly after birth from cardiac abnormalities with extensive DNA damage and p53 activation, and AAV-mediated cardiomyocyte-specific Lemd2 delivery rescues cardiac function.
"We generated knockin (KI) mice carrying the human c.T38>G Lemd2 mutation, which causes a missense amino acid exchange (p.L13>R) in the LEM domain of the protein. These mice represent a preclinical model that phenocopies the human disease, as they developed severe dilated cardiomyopathy and cardiac fibrosis leading to premature death. At the cellular level, KI/KI cardiomyocytes exhibited disorganization of the transcriptionally silent heterochromatin associated with the nuclear envelope. Moreover, mice with cardiac-specific deletion of Lemd2 also died shortly after birth due to heart abnormalities. Cardiomyocytes lacking Lemd2 displayed nuclear envelope deformations and extensive DNA damage and apoptosis linked to p53 activation. Importantly, cardiomyocyte-specific Lemd2 gene therapy via adeno-associated virus rescued cardiac function in KI/KI mice."
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LEMD2 is an INM protein with a LEM domain and two transmembrane domains that mediates interaction between chromatin and the NE via association with lamins and BAF.
"LEM domain–containing protein 2 (LEMD2), which is expressed ubiquitously, is characterized by the presence of the LEM domain and 2 transmembrane domains. A series of in vitro studies revealed its ability to associate with DNA-binding proteins such as lamins and barrier-to-autointegration factor (BAF), which implicates LEMD2 as a mediator of the interaction between chromatin and the NE"
Nuclear envelope assembly relies on CHMP-7 in the absence of BAF-LEM-mediated hole closure.
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LEMD2 contributes to NE sealing through its C-terminal winged helix (WH) domain, which directly binds and activates CHMP7; the WH of LEMD2 copolymerizes with CHMP7 to form 50-100 nm rings on the cytosolic surface of NE holes to restrict diffusion. The WH domain of LEM-2 (C. elegans LEMD2 homolog) recruits CHMP-7 to the NE; LEM-2-CHMP-7 function is essential for NE assembly when BAF-LEM binding is compromised.
"The LEM-domain protein LEMD2 contributes to NE sealing through its C-terminal winged helix (WH) domain, which directly binds and activates the conserved endosomal sorting complex required for transport (ESCRT)-II/ESCRT-III hybrid protein CHMP7 (Gatta et al., 2021; Gu et al., 2017; von Appen et al., 2020). The WH of LEMD2 copolymerizes with CHMP7 to form 50–100 nm rings in vitro and it is thought that the assembly of these rings on the cytosolic surface of NE holes restricts the diffusion of macromolecules"
Micronuclear collapse from oxidative damage.
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Mitochondria-derived ROS disrupt micronuclear integrity through a pathological axis in which ROS-induced cysteine oxidation stimulates CHMP7 oligomerization and aberrant binding to LEMD2, disrupting micronuclear envelopes and engendering chromosome shattering. This axis mediates micronuclear disintegrity under hypoxic conditions, linking tumor microenvironment stress to aberrant engagement of the LEMD2-CHMP7 module.
"ROS-induced cysteine oxidation stimulated CHMP7 oligomerization and binding to the nuclear membrane protein LEMD2, disrupting micronuclear envelopes. Furthermore, this ROS-CHMP7 pathological axis engendered chromosome shattering known to result from micronuclear rupture. It also mediated micronuclear disintegrity under hypoxic conditions, linking tumor microenvironment"
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The ESCRT-III complex mediates nuclear envelope repair by assembling through binding to LEMD2 and CHMP7 scaffolds at nuclear membrane rupture sites.
"The endosomal sorting complex required for transport III (ESCRT-III) complex is a key player in mediating nuclear envelope repair, and it assembles through binding to LEM domain nuclear envelope protein 2 (LEMD2) and charged multivesicular body protein 7 (CHMP7) scaffolds at the nuclear membrane rupture sites"
Deep research on LEMD2 function (falcon)
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LEMD2/LEM2 acts as a chromatin-lamina-ESCRT integrator at the inner nuclear membrane; its N-terminal LEM domain binds BAF and lamins, a low-complexity region undergoes liquid-liquid phase separation at spindle-associated membrane gaps, and the C-terminal winged-helix/MSC domain binds and activates CHMP7 to nucleate ESCRT-III-mediated NE sealing. The CHMP7/LEMD2 module preferentially seals small NE holes (<100 nm), while BAF-driven mechanisms dominate at larger ruptures.
"Mechanistically, LEM2/LEMD2 can recruit/activate CHMP7 via a C-terminal WH/MSC domain; CHMP7 then nucleates downstream ESCRT-III assembly for membrane sealing."
Overlapping functions of nuclear envelope proteins NET25 (Lem2) and emerin in regulation of extracellular signal-regulated kinase signaling in myoblast differentiation.
Defining the membrane proteome of NK cells.
LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope closure in fission yeast and human cells.
Architecture of the human interactome defines protein communities and disease networks.
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
VPS4 binds ESCRT-III assemblies at nuclear envelope (NE) fenestrations
CHMP7 binds CHMP4B, which recruits other subunits of the ESCRT-III complex
SPAST (spastin) binds the IST1 subunit of ESCRT-III at the sites of microtubule attachment to chromatin
VPS4 mediates disassembly of ESCRTIII subunits to promote sealing of holes in the nuclear envelope
SPAST (spastin) mediates the severing of microtubules at chromosome attachment sites
Deep research on LEMD2 function