Menin-SETD2, mapped to the NTD and Palm and tooled with a peptide at menin 231-248: the third partner assigned to the same half of menin, and the writer arm of the HR scaffold
also called Pep242 · menin 231-248 · menin-SETD2 interface
Menin holds SETD2, the enzyme that writes the H3K36me3 mark used to guide accurate DNA repair, and a short menin peptide covering residues 231 to 248 is used as a tool to break that hold. This is the enzyme half of the repair scaffold whose histone-binding half is menin's 371-400 motif.
The same thing, for a scientist
Zhu et al. report that menin interacts directly with SETD2 through its N-terminal domain (NTD) and Palm domains to maintain SETD2 protein stability and chromatin recruitment, and that menin and SETD2 together sustain CSF2 expression through H3K36me3 in alveolar macrophages. The same group's 2026 HR paper uses a cell-penetrating peptide, Pep242, covering **menin amino acids 231-248**, as the menin-SETD2 disrupting tool alongside Pep-MH (371-400) as the menin-H2A.X disrupting tool - so the two arms of the proposed scaffold have two different peptide tools at two non-overlapping menin windows. Menin 231-248 is DRKMEVAFMVCAINPSID in the live O00255 sequence; residues 232-241 form a helix and 246-248 a beta strand in the deposited structures, and 238, 241, 242, 244, 246-249 are within 4.5 A of the bound KMT2A MBM1 peptide in 4GQ6 - so this window, too, overlaps the central cavity.
No three-dimensional model is available for this protein, so the map above is the whole picture. That is itself informative: AlphaFold does not model chains this long, and the parts that have been crystallised are held under the entries for the individual domains.
The scaffold, and where each arm sits on menin
The 2026 model is a relay: menin reads gamma-H2A.X at a break, recruits SETD2 to write H3K36me3, LEDGF reads H3K36me3, LEDGF recruits CtIP for end resection, and resection activates RPA2/Rad51 2. Menin therefore needs at least three simultaneous contacts, and this beat can now place all three:
| arm | menin residues | evidence class | distance to the drug pocket |
|---|---|---|---|
| gamma-H2A.X (the mark) | 371-400 | truncation + deletion + peptide | V371 is 2.3-4.3 A from three of four clinical compounds |
| SETD2 (the writer) | NTD + Palm; tool peptide 231-248 | co-IP domain mapping + a peptide tool | menin 238-249 are 3.0-4.2 A from the MBM1 peptide in 4GQ6 |
| LEDGF (the reader) | 91-105 and 209-212 | X-ray, 3U88 | 22.8-37.9 A, no contact with any compound |
Two of the three arms touch the cavity and one does not. That is the shape of the drug question for this scaffold, and it is not resolvable from domain names.
Why Pep242's window is worth recording separately
Pep242 is described in the 2026 methods as "covering amino acids 231-248 of menin", fused to octa-arginine, and cited to the group's 2025 macrophage paper 21. Menin 231-248 reads DRKMEVAFMVCAINPSID in the live O00255 sequence, spans a helix at 232-241 and a beta strand at 246-248 in the deposited secondary structure, and includes residues 238, 241, 242, 244 and 246-249 that contact the KMT2A MBM1 peptide in the 1.55 A structure 4GQ6 3.
So a peptide sold as a menin-SETD2 disruptor covers part of the KMT2A-binding cavity. Whatever it does in cells, it is not a clean separation-of-function reagent for the SETD2 arm, and any experiment that uses it to argue "the SETD2 contact specifically" needs a KMT2A-binding control that has not been reported.
| partner a | gene-men1 |
|---|---|
| partner b | gene-setd2 |
| motif a | menin N-terminal domain plus Palm domain (no residue coordinates published in any source read here); the disrupting peptide tool covers menin 231-248 |
| motif b | not mapped |
| interface residues a note | NONE published. The only numeric window associated with this contact is the Pep242 tool peptide's 231-248, which is a reagent boundary and not an interface map. |
| method that mapped it | co-immunoprecipitation with menin domain constructs (2025); a cell-penetrating peptide tool covering 231-248 (2025, reused 2026) |
| pep242 sequence readback | DRKMEVAFMVCAINPSID (O00255 residues 231-248, fetched 2026-09-22) |
| ligand note | revumenib contacts menin 238, 241 and 242 at 3.3-3.5 A in 7UJ4, i.e. three residues inside the Pep242 window. Whether that has any bearing on the SETD2 contact is unknown because the SETD2 contact has no residue map. |
| epigenetic readout | menin stabilises and recruits the H3K36me3 WRITER SETD2; downstream H3K36me3 is read by LEDGF |
| shown for fusion | NO. Mouse alveolar macrophages and lung (2025); A549, MEFs and mouse lung (2026). No KMT2A-rearranged cell, no leukaemia. |
| cell type | mouse alveolar macrophages and myeloid lineage (2025); human A549 and mouse embryonic fibroblasts (2026) |
| relationship to existing entries | New for the menin side. `gene-setd2` exists; nothing in this graph places SETD2 on menin, and nothing records the Pep242 window. Related to `interface-menin-h2ax-val371-gln400` (the other arm of the same scaffold, from the same paper) and to `interface-menin-ledgf-ibd-menin-side-91-105` (the reader arm). |
interface residues a
[]
interface residues b
[]
domains
[
{
"name": "Pep242 window (menin 231-248)",
"start": 231,
"end": 248
}
]structures
[]
structures absent
[ "no PDB deposit contains menin with SETD2", "no numeric boundary for menin's NTD, thumb, palm or fingers domains appears in any source this beat could read - Huang et al. define them in a supplementary figure that was not retrievable" ]
overlap with the mbm cavity
{
"menin_residues_in_231_248_within_4_5A_of_the_KMT2A_MBM1_peptide_in_4GQ6": [
238,
241,
242,
244,
246,
247,
248
],
"consequence": "Pep242 is not a clean separation-of-function reagent for the SETD2 arm; a KMT2A-binding control has not been reported for it"
}ligands
[ "drug-revumenib", "drug-ziftomenib" ]
- If menin stabilises SETD2, then removing menin lowers a writer whose loss is separately associated with leukaemia - so a menin-directed therapy has a mechanism to reduce H3K36me3 globally, and nobody has measured H3K36me3 under a menin inhibitor in any system.
- The peptide tools that define this biology are cationic cell-penetrating peptides at two different menin windows, one of which overlaps the drug pocket's contact surface. Conclusions drawn from them need the controls that have not been published.
- Delivery and specificity: proposing to block a menin-SETD2 contact means proposing a peptide, and the only such peptide in the literature is not separation-of-function.
- A menin degrader would remove the writer-stabilising function too, adding an H3K36me3 arm to the repair concern that the gamma-H2A.X arm already raises.
- What are the numeric boundaries of menin's NTD, thumb, palm and fingers? Every paper since 2012 uses these names and the boundaries live in one supplementary figure. Deriving them from the deposited coordinates would let this graph place every domain-level menin claim on a residue axis, and it is a day's work.
- Does Pep242 disturb the menin-KMT2A contact? Seven of its eighteen residues sit on the MBM1 contact surface in folded menin, and no control for this has been reported.
- Is the menin-SETD2 contact direct? 'Interacts directly' in the abstract rests on co-IP in the readable material; a recombinant pulldown or an affinity would settle it.
- Is any of this true in a haematopoietic cell? The menin-SETD2-LEDGF relay is established in lung and fibroblast systems, and LEDGF is already central to this graph for a completely different reason.
- E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Menin interacts directly with SETD2 through its N-terminal domain (NTD) and Palm domains to maintain SETD2 protein stability and chromatin recruitment; menin and SETD2 together maintain CSF2 expression through H3K36me3, and myeloid Men1 deletion causes spontaneous pulmonary alveolar proteinosis through impaired alveolar macrophage development.
Menin orchestrates macrophage reprogramming to maintain the pulmonary immune homeostasis. · Zhu X, Xu B, Lian A, Zhang X, Wang Y, Zhang Y, Zhang L, Ma J, Gao S, Jin G · Cell Rep 2025What this evidence cannot show
Cited at ABSTRACT level: the efetch abstract was fetched and read on 2026-09-22; the full text was not opened. 'NTD and Palm domains' is a domain-name assignment with no residue coordinates in the abstract, and Huang et al.'s numeric boundaries for the NTD, thumb, palm and fingers are in a supplementary figure this beat could not retrieve - so NO residue range is asserted here for the SETD2 contact itself. Mouse myeloid system, lung; not a leukaemia, not a KMT2A fusion, not a human cell.
Evidence that argues against this (1)
- A menin-SETD2 contact placed in the NTD and Palm overlaps in domain terms with the Palm/Fingers placement the same group gives for the gamma-H2A.X contact, and with the central cavity that binds KMT2A and JUND. Three functions on overlapping domain assignments from one laboratory, with no competition experiment between them, is the situation in which domain-level mapping stops discriminating - the same defect this beat documents for the SvID. Lian A et al. 2026
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Menin acts as the scaffold of an H3K36me3-dependent HR relay - menin recruits SETD2 to damage sites as the writer, LEDGF reads H3K36me3 and recruits CtIP as the effector for end resection, activating the RPA2/Rad51 pathway - and the study uses two cell-penetrating peptide tools: Pep242, covering menin amino acids 231-248, and Pep-MH, covering menin amino acids 371-400.
The tumor suppressor menin is a key scaffold mediator for homologous recombination repair. · Lian A, Zhu X, Jin B, Gu G, Xu B, Zhang L, Lin X, Zhu X, Jin G · Nucleic Acids Res 2026What this evidence cannot show
The Pep242 window is quoted verbatim from the Methods ('Pep242 [8] (covering amino acids 231-248 of menin)'), read from the Europe PMC fullTextXML on 2026-09-22. Both peptides carry an octa-arginine cell-penetrating tag, which is itself nucleic-acid- and chromatin-binding, and no scrambled-octa-arginine control is described for Pep242. The whole relay is established in A549 cells, Men1-knockout MEFs and Men1-floxed mice - no haematopoietic cell and no KMT2A fusion anywhere in the study.
Evidence that argues against this (1)
- LEDGF's role as an H3K36me3 reader that promotes DNA end resection and HR was established independently in 2012 (Daugaard et al., Nat Struct Mol Biol), and SETD2-dependent H3K36me3 was shown to be required for HR in 2014 (Pfister et al., Cell Rep). The 2026 paper's novelty is the menin scaffold, not the relay - so the relay would survive even if the menin arm did not, and this graph should not treat H3K36me3-dependent HR as menin-dependent by default. Daugaard M et al. 2012
- E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
Menin residues 231-248 read DRKMEVAFMVCAINPSID in the live O00255 sequence; the region spans a helix at 232-241 and a beta strand at 246-248 in the deposited secondary structure, and menin 238, 241, 242, 244 and 246-249 lie within 4.5 A of the bound KMT2A MBM1 peptide in the 1.55 A structure 4GQ6.
analyses/q34-menin-surface-geometry/run.py - menin surface geometry over all 69 O00255 PDB deposits · Q34-menin-surface-map · Oncofusion Knowledge Graph 2026What this evidence cannot show
Computed 2026-09-22 against live RCSB mmCIF and live UniProt; secondary-structure spans are UniProt's PDB-derived Helix and Beta strand features on O00255. The overlap between the Pep242 window and the MBM1 contact surface is a statement about where those residues are in FOLDED menin; a free 18-mer peptide is not folded menin and may not present the same surface. That cuts both ways - it weakens the worry about a KMT2A-competing side effect and it equally weakens any claim that Pep242 mimics the SETD2-binding surface.
Evidence that argues against this (1)
- An isolated linear peptide from the middle of a compact alpha-helical protein rarely recapitulates its native surface, so Pep242's cellular effects may be mediated by something other than the menin-SETD2 contact it is named for - including by its octa-arginine tag. This applies equally to Pep-MH, except that Pep-MH's window is largely disordered in the folded protein and so is more plausible as a free peptide. RCSB Protein Data Bank depositors 2026
menin NTD + Palm; Pep242 tool window 231-248
menin binds SETD2 and maintains its stability and chromatin recruitment
the writer arm of the same HR scaffold whose histone-reading arm is 371-400
SETD2 writes H3K36me3 and LEDGF reads it; both are menin contacts in the same relay
the writer arm of the same scaffold, also removed by a degrader and not by a pocket ligand
Pep242 covers menin 231-248, which this parse places at the thumb-palm boundary rather than inside either