Oncofusion

start / graph / interface-kmt2a-tmco1-declined-an-er-calcium-channel-crosslinked-in-nuclei

Interfaceweak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.Q129-the-never-discussed-partners-of-kmt2a-and-psip1

KMT2A-TMCO1 is a single DSSO crosslink in one detergent fraction of isolated U2OS nuclei with no bait on either side; TMCO1 is an ER-membrane calcium channel and the source paper attributes 4% of its links to nucleus-ER contamination - declined

also called KMT2A-TMCO1 · MLL-TMCO1 · CALCIUM LOAD-ACTIVATED CALCIUM CHANNEL · EBI-20903320

A database lists TMCO1, a calcium channel that sits in the membrane of the endoplasmic reticulum, as a KMT2A partner. The single supporting measurement is one chemical crosslink found in a detergent fraction of isolated nuclei, in a paper whose authors say some of their nucleus-to-ER links come from contamination during nuclei purification.

The same thing, for a scientist

**Verdict: DECLINED. Detection method is chemical crosslinking mass spectrometry (DSSO XL-MS), with no bait: both participants are recorded as 'neutral component'** [E1]. One IntAct record, EBI-20903320, from PMID 30021884, host U2OS osteosarcoma, intact-miscore 0.4, annotated to Table S2-pink and *'interaction detected in: TX100 soluble fraction (fractionated nuclei)'* - **one preparation only** [E1]. TMCO1 is UniProt Q9UM00, 239 aa, **Endoplasmic reticulum membrane [ECO:0000269] and Golgi apparatus membrane [ECO:0000269]**, plus mitochondrion membrane by similarity; it is an ER calcium-selective channel that oligomerises on ER Ca2+ overload to prevent store overfilling [E3]. **The specific control is the paper's own: 4% of its interactions are nucleus-endoplasmic-reticulum, part of a 30% cross-compartment fraction that the authors write 'could also be partly influenced by contamination with other subcellular compartments during our nuclei isolation'** [E2]. **This is the only one of KMT2A's five Fasci crosslink partners that is an integral membrane protein of the ER**, and one of two non-nuclear ones alongside ITGB1 [E4]. Neither 'KMT2A' nor 'TMCO1' appears anywhere in the paper's text [E2].

Go deeper
What a nuclear-envelope-adjacent crosslink would and would not mean

There is a version of this that is not contamination and it deserves to be stated, because the ER membrane is continuous with the outer nuclear membrane.

An ER-resident protein can be present in an intact-nuclei preparation legitimately, as part of the nuclear envelope. If TMCO1 sits in the inner or outer nuclear membrane, a crosslink to a nuclear protein is not physically absurd.

Three things stop that reading here.

  1. KMT2A is not a nuclear-envelope protein. Its recorded location is Nucleus (ECO:0000269) with two uncoded fragment comments; nothing places it at the lamina or the inner nuclear membrane 3. This graph has an entry on KMT2A and lamina-associated domains, and the relationship there is between the fusion's target genes and LADs, not between KMT2A and the membrane.
  2. The crosslink is in the Triton X-100 SOLUBLE fraction 1. Detergent-soluble is where the paper reports the non-chromatin material concentrates - it notes that histones were largely in the insoluble fraction and that the identifiable-nuclear share rose to 85% in the insoluble fraction 2. An integral membrane protein solubilised by Triton crosslinked to a chromatin protein, in the fraction where chromatin is depleted, is the weakest combination available in this dataset.
  3. It appears in one preparation, not two 1, against 58% replicate overlap in the dataset 2.

What would change it: the crosslinked lysine positions and PSM score from supplemental Table S2, which were not retrieved; or any independent placement of KMT2A at the nuclear envelope, which does not exist in this graph or in UniProt.

Facts and figures
partner agene-kmt2a
partner a uniprotQ03164
partner a length AA3969
partner bTMCO1
partner b uniprotQ9UM00
partner b length AA239
verdictDECLINED
adjudicated byQ129, cycle 92, 2026-09-23
source publication pmid30021884
source datasetFasci 2018 nuclear XL-MS (DSSO, U2OS intact nuclei)
detection methodchemical crosslinking mass spectrometry (DSSO XL-MS)
experimental role partnerneutral component
experimental role kmt2aneutral component
bait exists in datasetfalse
intact miscore0.4
n publications1
n methods1
orthogonal method existsfalse
dataset cross compartment PCT30
dataset nucleus er PCT4
druggabilityNot assessable. The crosslinked lysine positions - the one thing an XL-MS row could contribute to an interface map - are in supplemental Table S2 and were not retrieved.
absence classmeasured-not-searched
absence class noteThe decisive missing datum is the crosslinked lysine positions and PSM score for EBI-20903320, which sit in supplemental Table S2 of PMID 30021884 and in that paper's PRIDE deposition; neither was opened. That is an afternoon, not an experiment. The separate never-measured absence is that no experiment has tested KMT2A against TMCO1 with KMT2A as bait, in any cell.
shown for fusionNO - nobody has looked in any KMT2A fusion. U2OS osteosarcoma nuclei; no fusion protein present.
epigenetic readoutnone - no histone mark, occupancy or chromatin measurement exists for this pair.
host cell lines
[
  "U2OS osteosarcoma"
]
preparations detected in
[
  "TX100 soluble fraction (fractionated nuclei)"
]
records
[
  "EBI-20903320"
]
compartment mismatch
{
  "partner_compartments": [
    "Endoplasmic reticulum membrane [ECO:0000269]",
    "Golgi apparatus membrane [ECO:0000269]",
    "Mitochondrion membrane [ECO:0000250]"
  ],
  "partner_nuclear_annotation": "none at any evidence level",
  "kmt2a_membrane_or_envelope_annotation": "none at any evidence level",
  "caveat": "the ER membrane is continuous with the outer nuclear membrane, so the mismatch is not absolute"
}
interface residues a
[]
structures
[]
ligands
[
  "drug-revumenib",
  "drug-ziftomenib"
]
How this could bite us back
  • If any part of the KMT2A pathway ran through ER calcium handling, menin inhibitors would have an off-chromatin mechanism nobody monitors, and differentiation syndrome - the main on-target toxicity of that drug class - is an inflammatory syndrome in which calcium signalling is not implausible. This row is far too weak to support that and it is recorded so the idea is traceable rather than repeatable as fact.
  • Declining an ER partner should not harden into a rule that non-nuclear proteins cannot be relevant. The nuclear envelope is a real compartment with real chromatin contacts, and a blanket compartment filter would delete genuine envelope biology along with the noise.
Still open
  1. Is KMT2A ever at the nuclear envelope? This graph carries subnuclear localisation as an explicit PI dimension and has an entry on lamina-associated domains, but nothing places KMT2A itself at the envelope or excludes it. That absence is what makes this row hard to dismiss cleanly rather than easy.
  2. Would applying a compartment filter to all 4,856 Fasci rows produce a usable nuclear subnetwork for this project? The dataset is good for nuclear complexes and this beat only touched its weakest corner.
  3. Do the crosslinked lysines in Table S2 fall in any annotated KMT2A domain? If they fall in the disordered central region the row becomes even less informative; if they fall in a structured domain it becomes a testable constraint.
Every source behind this entry (4)
  1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    IntAct curates one record of a KMT2A-TMCO1 physical association, EBI-20903320, from PMID 30021884. Detection method 'crosslink' (XL-MS), interaction type 'physical association', NO expansion method, host Homo sapiens U2OS osteosarcoma cell. Both TMCO1 (Q9UM00) and KMT2A (Q03164) are recorded as 'neutral component' - there is no bait and no prey. intact-miscore 0.4. Annotations: 'figure legend (Table S2-pink)' and 'comment (interaction detected in: TX100 soluble fraction (fractionated nuclei))' - one preparation only.

    What this evidence cannot show

    Read live from IntAct REST on 2026-09-23, not PSICQUIC (rule 93). Supplemental Table S2 was not opened, so the crosslinked residue positions, the PSM score and the meaning of the 'pink' colour code are unknown here. The annotation names one preparation; whether that reflects one spectrum or several was not determined.

    Evidence that argues against this (1)
    • A crosslink is a physical distance restraint formed in situ before lysis, which is in principle better evidence than a spoke-expanded affinity row. Unlike the eight AP-MS partners in this beat, this record does not depend on a tagged over-expressed bait surviving a wash, and IntAct records no expansion for it. IntAct (EMBL-EBI) 2026
  2. E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

    In isolated intact human U2OS nuclei, Fasci et al. crosslinked with DSSO and identified ~8,710 unique crosslinks at 1% FDR, ~58% overlapping between two independent biological replicates, to a reliable detection depth of ~1.5e4 protein copies per cell. Histones were largely detected in the Triton X-100 insoluble fraction and the identifiable-nuclear share of crosslinks rose to 85% in that insoluble fraction. The paper states: '20% of the interactions were nucleus-cytosol/plasma membrane, 6% nucleus-mitochondria and 4% nucleus-endoplasmic reticulum. This result is in line with the multiple subcellular localization reported for many proteins but could also be partly influenced by contamination with other subcellular compartments during our nuclei isolation.'

    Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei. · Fasci D, van Ingen H, Scheltema RA, Heck AJR · Molecular & cellular proteomics : MCP 2018
    PMID 30021884DOI
    What this evidence cannot show

    Full text read 2026-09-23 through the PMC HTML route (PMC6166682, 92,127 stripped characters) after fullTextXML returned HTTP 500 and efetch db=pmc returned a body-less document. The strings 'KMT2A', 'MLL' and 'TMCO1' each appear ZERO times in the paper's text; this row exists only in a supplementary table that was not opened. The inference that Triton-soluble is the chromatin-depleted fraction is drawn from the paper's statements about histone partitioning and about the insoluble fraction's higher nuclear share - the paper does not make that inference about TMCO1 or about this row.

    Evidence that argues against this (1)
    • The paper's contamination sentence offers two readings and puts genuine multi-compartment localisation first. TMCO1 does have a documented Golgi pool as well as ER, so it is a protein that moves between membranes, and 'contamination' is an interpretation of its presence rather than an observation. Fasci D et al. 2018
  3. E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    UniProtKB Q9UM00 is 239 aa, primary gene name TMCO1, recommended name 'Calcium load-activated calcium channel'. Subcellular location: Endoplasmic reticulum membrane [ECO:0000269], Golgi apparatus membrane [ECO:0000269], Mitochondrion membrane [ECO:0000250]; there is no nuclear comment at any evidence level. Function: ER calcium-selective channel that prevents intracellular Ca2+ stores from overfilling, assembling into a homotetramer on ER Ca2+ overload. Tissue specificity: widely expressed in adult and fetal tissues. KMT2A (Q03164) is 3,969 aa with one ECO:0000269 Nucleus comment plus two uncoded comments for the N320 and C180 taspase1 cleavage products, and no nuclear-envelope or membrane annotation.

    What this evidence cannot show

    UniProt location comments are curated pointers, not measurements (rule 91); the cited papers were not opened. The ER membrane is continuous with the outer nuclear membrane, so an ER annotation does not by itself exclude presence in a nuclear preparation - the argument used here is the conjunction of that with KMT2A having no membrane or envelope annotation, and with the crosslink being in the detergent-soluble fraction.

    Evidence that argues against this (1)
    • TMCO1 is widely expressed including in haematopoietic tissue, and loss-of-function causes a developmental syndrome, so it is not an obscure protein. Calcium signalling at the nuclear envelope is a real field. The decline rests on the quality of this single record, not on a claim that TMCO1 could never be near chromatin. UniProt Consortium 2026
  4. E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    IntAct serves 4,856 rows from PMID 30021884 across 3,660 distinct molecules, every row 'crosslink' with both participants as 'neutral component' and no spoke expansion. Within that dataset KMT2A has exactly five crosslink partners - CCT6A, ITGB1, NPM1, RPL13 and TMCO1 - of which two, ITGB1 (plasma membrane) and TMCO1 (ER/Golgi membrane), are UniProt-annotated membrane proteins.

    What this evidence cannot show

    Instrument note: the IntAct REST endpoint returns 0 for the field-scoped form `pubid:30021884` and 4,856 for the bare PMID as free text - a clean, well-formed false zero of the same shape as rules 85 and 95. Rows were filtered on publicationPubmedIdentifier before counting. Two of five is a denominator of five and carries no statistical weight; it is stated as a description of KMT2A's neighbourhood in this dataset, not as an enrichment.

    Evidence that argues against this (1)
    • The other three of KMT2A's five Fasci partners are NPM1, RPL13 and CCT6A - a nucleolar chaperone, a ribosomal protein and a CCT/TRiC chaperonin subunit. NPM1 in particular is a genuine abundant nucleolar protein and its presence is not absurd, so the dataset's KMT2A neighbourhood is not uniformly implausible. IntAct (EMBL-EBI) 2026
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