LEM domain-containing protein 2, transmembrane protein of inner nuclear membrane (INM) essential for nuclear envelope integrity, chromatin organization, and cardiac function. Contains highly conserved LEM domain mediating interactions with BAF (barrier-to-autointegration factor) and lamins, plus two transmembrane domains anchoring it to INM. Acts as transmembrane adapter for ESCRT (endosomal sorting complexes required for transport) machinery, recruiting proteins CHMP7, IST1/CHMP8, and CHMP2A to facilitate nuclear envelope closure during cell division and repair. Critical for detecting and repairing nuclear envelope ruptures both during mitotic exit and interphase by recruiting ESCRT-III components. Interacts with DNA-binding proteins (lamins and BAF), mediating connection between chromatin and nuclear envelope. Helps organize heterochromatin at NE, influencing gene expression and maintaining genome stability. Regulates signaling pathways MAPK/ERK and AKT, required for myoblast differentiation and cardiac homeostasis. Essential for embryogenesis, particularly proper heart development. Localized to inner nuclear membrane where it associates with nuclear lamina and chromatin. Known interactions: Lamins A/C (nuclear lamina structural proteins), BAF (DNA-binding protein for chromatin organization), ESCRT-III components (NE reformation and repair), signaling molecules (modulates ERK and AKT pathways in muscle/cardiac cells). Homozygous missense mutations (e.g. c.T38>G, p.L13R in LEM domain) linked to arrhythmic cardiomyopathy, cataracts, and sudden death. Loss of function causes severe cardiac defects, nuclear envelope deformations, DNA damage, and apoptosis via p53 activation. LEMD2 deficiency leads to widespread gene expression changes, activation of p53-dependent DNA damage response, and cardiomyocyte apoptosis. Mutations cause dilated cardiomyopathy, cardiac fibrosis, and cataract 46. Role in nuclear envelope surveillance and ESCRT-mediated repair is central to maintaining cellular homeostasis, especially under mechanical stress. Gene therapy approaches show rescue of cardiac defects in animal models.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0071763 nuclear membrane organization | IBA GO_REF:0000033 | ACCEPT | Summary: Nuclear membrane organization - core function. LEMD2/LEM2 closes nuclear envelope holes around spindle microtubules together with CHMP7, and its C-terminal winged-helix domain copolymerizes with CHMP7 into 50-100 nm rings that restrict diffusion at NE holes. Reason: Primary process supported by multiple mechanistic studies. Supporting Evidence: file:human/LEMD2/LEMD2-deep-research-perplexity-lite.md See deep research file for comprehensive analysis file:human/LEMD2/LEMD2-deep-research-falcon.md LEMD2 is described as a ubiquitously expressed INM protein with a conserved N-terminal LEM domain and two transmembrane segments, localizing at the nuclear periphery. Its LEM domain enables association with DNA-associated proteins including lamins and BAF, supporting a chromatin–nuclear envelope tethering function. PMID:37795681 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 |
| GO:0005637 nuclear inner membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Nuclear inner membrane - specific INM protein. Reason: Core localization. |
| GO:0034399 nuclear periphery | IBA GO_REF:0000033 | ACCEPT | Summary: Nuclear periphery - INM localization. Reason: Core localization. |
| GO:0005635 nuclear envelope | IEA GO_REF:0000044 | ACCEPT | Summary: Nuclear envelope - core localization. Reason: Primary localization. |
| GO:0005637 nuclear inner membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Nuclear inner membrane - specific INM protein. Reason: Core localization. |
| GO:0005819 spindle | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Spindle - NE reformation during mitosis. Reason: Cell division context. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: Protein binding from HTP interactome study - generic term per CLAUDE.md guidance, more informative MFs (GO:0030674 protein-macromolecule adaptor activity in core_functions) capture the actual scaffold/adapter role. Reason: Per CLAUDE.md, avoid the generic protein-binding term when more specific MFs are available; PR Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Protein binding from HTP interactome study - generic term per CLAUDE.md guidance, more informative MFs (GO:0030674 protein-macromolecule adaptor activity in core_functions) capture the actual scaffold/adapter role. Reason: Per CLAUDE.md, avoid the generic protein-binding term when more specific MFs are available; PR Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. |
| GO:0022008 neurogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Neurogenesis - developmental role. Reason: Broad developmental process. |
| GO:0031965 nuclear membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Nuclear membrane - general NE localization. Reason: Core localization. |
| GO:0035914 skeletal muscle cell differentiation | IEA GO_REF:0000120 | ACCEPT | Summary: Skeletal muscle cell differentiation - myoblast differentiation. Reason: Differentiation role. |
| GO:0043409 negative regulation of MAPK cascade | IEA GO_REF:0000107 | ACCEPT | Summary: Negative regulation of MAPK cascade - regulates ERK pathway. Reason: Signaling regulation. |
| GO:0051898 negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | IEA GO_REF:0000107 | ACCEPT | Summary: Negative regulation of PI3K/AKT signaling. Reason: Signaling regulation. |
| GO:0060914 heart formation | IEA GO_REF:0000107 | ACCEPT | Summary: Heart formation - essential for cardiac development. Knockin mice with the human p.L13R LEM-domain mutation develop dilated cardiomyopathy and cardiac fibrosis; cardiomyocyte-specific Lemd2 KO mice die in the neonatal period from cardiac abnormalities. Reason: Core cardiac role supported by KI and conditional KO mouse models. Supporting Evidence: PMID:36377660 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. file:human/LEMD2/LEMD2-deep-research-falcon.md A 2022 Journal of Clinical Investigation study created a knock-in mouse carrying the human disease allele c.T38>G (p.L13R) and showed severe dilated cardiomyopathy and fibrosis. Importantly, cardiomyocyte-specific AAV-mediated Lemd2 gene therapy rescued cardiac function in KI/KI mice. |
| GO:0031965 nuclear membrane | IDA GO_REF:0000052 | ACCEPT | Summary: Nuclear membrane - general NE localization. Reason: Core localization. |
| GO:0000785 chromatin | IDA PMID:28242692 LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope clos... | ACCEPT | Summary: Chromatin - organizes heterochromatin at NE. Cardiomyocyte-specific loss of LEMD2 disorganizes the transcriptionally silent heterochromatin associated with the nuclear envelope. Reason: Core function supported by mouse models. Supporting Evidence: PMID:28242692 LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope closure in fission yeast and human cells. PMID:36377660 At the cellular level, KI/KI cardiomyocytes exhibited disorganization of the transcriptionally silent heterochromatin associated with the nuclear envelope. |
| GO:0005635 nuclear envelope | IDA PMID:28242692 LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope clos... | ACCEPT | Summary: Nuclear envelope - core localization. Reason: Primary localization. Supporting Evidence: PMID:28242692 LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope closure in fission yeast and human cells. |
| GO:0005783 endoplasmic reticulum | IDA PMID:28242692 LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope clos... | KEEP AS NON CORE | Summary: ER - INM is continuous with ER but distinct. Reason: Related but distinct compartment. Supporting Evidence: PMID:28242692 LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope closure in fission yeast and human cells. |
| GO:0016020 membrane | TAS PMID:28242692 LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope clos... | ACCEPT | Summary: Membrane - transmembrane protein. Reason: General membrane. Supporting Evidence: PMID:28242692 LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope closure in fission yeast and human cells. |
| GO:0071168 protein localization to chromatin | IMP PMID:28242692 LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope clos... | KEEP AS NON CORE | Summary: Protein localization to chromatin annotation — the original PMID:28242692 reference is about ESCRT-mediated NE closure, NOT chromatin tethering (PR #758 review feedback). The biologically valid support for chromatin- tethering comes from LEMD2's LEM-domain interactions with BAF and lamins (the chromatin–NE tethering axis), captured separately by GO:0000785 chromatin and supported by PMID:36377660 below. Annotation kept as KEEP_AS_NON_CORE pending re-citation; the original PMID:28242692 supporting_text does not address chromatin-localization mechanism. Reason: The annotation is biologically plausible (via LEM-domain-BAF tethering), but the original PMID:28242692 reference does not directly establish chromatin localization; downgraded from ACCEPT pending a primary reference that directly demonstrates LEMD2-mediated chromatin protein localization. |
| GO:0005515 protein binding | IPI PMID:28242692 LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope clos... | MARK AS OVER ANNOTATED | Summary: Protein binding from HTP interactome study - generic term per CLAUDE.md guidance, more informative MFs (GO:0030674 protein-macromolecule adaptor activity in core_functions) capture the actual scaffold/adapter role. Reason: Per CLAUDE.md, avoid the generic protein-binding term when more specific MFs are available; PR Supporting Evidence: PMID:28242692 LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope closure in fission yeast and human cells. |
| GO:0005637 nuclear inner membrane | TAS PMID:28242692 LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope clos... | ACCEPT | Summary: Nuclear inner membrane - specific INM protein. Reason: Core localization. Supporting Evidence: PMID:28242692 LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope closure in fission yeast and human cells. |
| GO:0006998 nuclear envelope organization | IMP PMID:17097643 The inner nuclear membrane protein Lem2 is critical for norm... | ACCEPT | Summary: Nuclear envelope organization - primary function. LEMD2/LEM2 together with CHMP7 seals NE holes around spindle microtubules during mitotic exit; redundant with BAF-LEM-mediated hole closure. Reason: Core process supported by mechanistic studies in human cells and C. elegans. Supporting Evidence: PMID:17097643 Epub 2006 Nov 3. The inner nuclear membrane protein Lem2 is critical for normal nuclear envelope morphology. PMID:37795681 The LAP2-emerin-MAN1 (LEM)-domain protein LEMD2 and ESCRT-II/III hybrid protein CHMP7 close NE holes surrounding spindle microtubules (MTs). file:human/LEMD2/LEMD2-deep-research-falcon.md In nuclear-envelope maintenance, CHMP7 together with INM LEMD2 is implicated in sealing small nuclear-envelope holes, whereas repair of larger ruptures can depend more strongly on BAF-mediated mechanisms. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | ACCEPT | Summary: Membrane - transmembrane protein. Reason: General membrane. Supporting Evidence: PMID:19946888 Defining the membrane proteome of NK cells. |
| GO:0005635 nuclear envelope | TAS Reactome:R-HSA-9668335 | ACCEPT | Summary: Nuclear envelope - core localization. Reason: Primary localization. |
| GO:0005635 nuclear envelope | TAS Reactome:R-HSA-9668389 | ACCEPT | Summary: Nuclear envelope - core localization. Reason: Primary localization. |
| GO:0005635 nuclear envelope | TAS Reactome:R-HSA-9668395 | ACCEPT | Summary: Nuclear envelope - core localization. Reason: Primary localization. |
| GO:0005635 nuclear envelope | TAS Reactome:R-HSA-9668398 | ACCEPT | Summary: Nuclear envelope - core localization. Reason: Primary localization. |
| GO:0005635 nuclear envelope | TAS Reactome:R-HSA-9668405 | ACCEPT | Summary: Nuclear envelope - core localization. Reason: Primary localization. |
| GO:0005635 nuclear envelope | TAS Reactome:R-HSA-9668415 | ACCEPT | Summary: Nuclear envelope - core localization. Reason: Primary localization. |
| GO:0005635 nuclear envelope | TAS Reactome:R-HSA-9668419 | ACCEPT | Summary: Nuclear envelope - core localization. Reason: Primary localization. |
| GO:0005637 nuclear inner membrane | IDA PMID:16339967 LEM2 is a novel MAN1-related inner nuclear membrane protein ... | ACCEPT | Summary: Nuclear inner membrane - specific INM protein. Reason: Core localization. Supporting Evidence: PMID:16339967 LEM2 is a novel MAN1-related inner nuclear membrane protein associated with A-type lamins. |
| GO:0035914 skeletal muscle cell differentiation | IGI PMID:19720741 Overlapping functions of nuclear envelope proteins NET25 (Le... | ACCEPT | Summary: Skeletal muscle cell differentiation - myoblast differentiation. Reason: Differentiation role. Supporting Evidence: PMID:19720741 Aug 31. Overlapping functions of nuclear envelope proteins NET25 (Lem2) and emerin in regulation of extracellular signal-regulated kinase signaling in myoblast differentiation. |
| GO:0006325 chromatin organization | NAS | NEW | Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: file:human/LEMD2/LEMD2-uniprot.txt LEMD2 is INM protein with LEM domain. Essential for NE integrity and repair via ESCRT. Mutations cause arrhythmic cardiomyopathy. |
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