| Domain/region (approx. position) | Key binding partners | Cellular process/function | Key evidence (paper, year, DOI/URL) | Notes |
|---|---|---|---|---|
| N-terminal LEM domain (~40 aa motif; pathogenic p.L13R falls within this region) | BAF; lamins/chromatin-associated proteins | Tethers chromatin/heterochromatin to the inner nuclear membrane (INM); contributes to nuclear envelope (NE) integrity, chromatin stabilization, and post-mitotic NE reformation | Caravia et al., 2022, *J Clin Invest*, https://doi.org/10.1172/jci158897; Nair et al., 2025, *Nucleus*, https://doi.org/10.1080/19491034.2024.2449520 (pqac-00000023, pqac-00000025) | LEM domain is described as a ~40 aa bihelical BAF-binding motif in LEM-family proteins; p.L13R reduces function and is associated with cardiomyopathy phenotypes (pqac-00000023, pqac-00000025, pqac-00000053). |
| N-terminal region / LEM-domain-containing chromatin-targeting module (NTD; includes LEM domain) | BAF-coated chromatin | Targets LEMD2/LEM2 to anaphase chromatin and reforming NE; helps establish early nucleocytoplasmic compartmentalization | Johnson/von Appen, 2020, mechanistic LEM2 study (DOI not available in retrieved text); Keeley & Coyne, 2024, *Nucleus*, https://doi.org/10.1080/19491034.2024.2349085 (pqac-00000021, pqac-00000027, pqac-00000048) | In mechanistic models, BAF–LEM engagement positions LEM2 at NE holes/fenestrations before ESCRT-III recruitment; 2024 review notes CHMP7/LEMD2 mainly seal small holes, while larger ruptures rely more on BAF-mediated mechanisms (pqac-00000021, pqac-00000048). |
| Low-complexity domain (LCD) / phase-separating region (approx. aa 43–202; NTD aa 1–208 in LEM2 study) | Microtubules; chromatin-proximal membrane environment | Promotes local condensation/phase separation at spindle-associated membrane gaps during mitotic NE reformation; helps spatially organize membrane sealing machinery | Johnson/von Appen, 2020, mechanistic LEM2 study (DOI not available in retrieved text); Borah et al., 2022, *Front Cell Dev Biol*, https://doi.org/10.3389/fcell.2022.989217 (pqac-00000021, pqac-00000024, pqac-00000028) | Undergoes liquid-like phase separation; contains a microtubule-targeting/basic subregion; phosphomimetic changes block condensation, implying cell-cycle regulation (pqac-00000021, pqac-00000024). |
| Proline/arginine-rich microtubule-binding segment near first transmembrane helix (exact aa not fully resolved in retrieved evidence) | Spindle microtubules | Couples NE reformation to spindle disassembly/clearance; concentrates LEM2 at microtubule-occupied fenestrations | Johnson/von Appen, 2020, mechanistic LEM2 study (DOI not available in retrieved text) (pqac-00000021, pqac-00000024) | Supports a model in which LEMD2 bridges membranes, chromatin, and spindle microtubules to prevent persistent NE openings and genome damage (pqac-00000021, pqac-00000024). |
| Two transmembrane segments / membrane-embedded core | INM membrane environment; nuclear lamina-associated network | Anchors LEMD2 as an integral INM protein, enabling it to act as a chromatin–lamina tether and compartmentalization sensor at NE ruptures | Caravia et al., 2022, *J Clin Invest*, https://doi.org/10.1172/jci158897; Nair et al., 2025, *Nucleus*, https://doi.org/10.1080/19491034.2024.2449520; Borah et al., 2022, *Front Cell Dev Biol*, https://doi.org/10.3389/fcell.2022.989217 (pqac-00000010, pqac-00000023, pqac-00000025, pqac-00000022) | Caravia explicitly describes LEMD2 as an INM protein with two transmembrane segments; family reviews place LEMD2 among INM LEM proteins that cooperate with lamins and ESCRT pathways (pqac-00000010, pqac-00000023, pqac-00000025). |
| C-terminal winged-helix (WH) / MSC / MAN1-like domain (AA ~395–503 in LEM2 study) | CHMP7 directly; downstream ESCRT-III factors indirectly (e.g., IST1) | Recruits and activates CHMP7; nucleates ESCRT-III assembly for NE sealing/reformation and rupture repair | Johnson/von Appen, 2020, mechanistic LEM2 study (DOI not available in retrieved text); Keeley & Coyne, 2024, *Nucleus*, https://doi.org/10.1080/19491034.2024.2349085 (pqac-00000001, pqac-00000021, pqac-00000027, pqac-00000048) | Direct CHMP7-binding interface; relieves CHMP7 autoinhibition and induces polymerization; central to sealing small NE holes (<100 nm) per 2024 review (pqac-00000001, pqac-00000027, pqac-00000048). |
| LEMD2–CHMP7 functional module at NE ruptures/interphase repair sites (multi-domain emergent activity rather than single motif) | CHMP7, ESCRT-III machinery, BAF-assisted rupture context | Acts as a compartmentalization sensor that initiates ESCRT-III-dependent membrane repair at exposed chromatin/ruptures | Borah et al., 2022, *Front Cell Dev Biol*, https://doi.org/10.3389/fcell.2022.989217; Keeley & Coyne, 2024, *Nucleus*, https://doi.org/10.1080/19491034.2024.2349085 (pqac-00000022, pqac-00000036, pqac-00000048) | Reviews synthesize LEMD2 as part of the conserved “LEM-ESCRT toolkit”; exposure of LEM proteins to cytosol after rupture activates/recruits CHMP7 and downstream ESCRT-III (pqac-00000022, pqac-00000036). |
| Full-length LEMD2/LEM2 as chromatin–lamina–ESCRT integrator | BAF, lamins, CHMP7, microtubules | Maintains genome stability by integrating chromatin tethering, lamina association, membrane remodeling, and NE repair/reformation | Caravia et al., 2022, *J Clin Invest*, https://doi.org/10.1172/jci158897; Johnson/von Appen, 2020; Nair et al., 2025, *Nucleus*, https://doi.org/10.1080/19491034.2024.2449520; Borah et al., 2022, *Front Cell Dev Biol*, https://doi.org/10.3389/fcell.2022.989217; Keeley & Coyne, 2024, *Nucleus*, https://doi.org/10.1080/19491034.2024.2349085 (pqac-00000010, pqac-00000021, pqac-00000023, pqac-00000025, pqac-00000022, pqac-00000036) | Loss of function causes NE deformation, DNA damage, p53 activation, apoptosis, and cardiomyopathy in vivo; this broader phenotype is consistent with failure of both structural tethering and ESCRT-coupled repair functions (pqac-00000010, pqac-00000023, pqac-00000036). |


*Table: This table maps the major structural regions of human LEMD2/LEM2 to their known binding partners and molecular functions at the inner nuclear membrane. It is useful for functional annotation because it links UniProt-style domain architecture to experimentally supported roles in chromatin tethering, microtubule-associated nuclear envelope reformation, and CHMP7/ESCRT-III-mediated repair.*