ZNF362 - the paralogue that makes the same leukaemia with the same partners, and that explains the six-zinc-finger convention
also called PP6997 · ZN362_HUMAN · zinc finger protein 362
ZNF362 is ZNF384's closest relative. Four children have been found with ZNF362 fusions instead, using the same partner genes, and their leukaemias look transcriptionally identical to the ZNF384 ones. It is the natural control for asking which parts of ZNF384 actually matter.
The same thing, for a scientist
ZNF362 (UniProtKB **Q5T0B9**, **420 aa**) is the paralogue of ZNF384; both belong to what Li et al. call the ZFAM4 family. Its feature table records **exactly six C2H2 zinc fingers at 227-249, 255-277, 283-305, 311-335, 341-363 and 371-393**, disordered regions at 1-28, 54-80, 115-155 and 178-202, and a nucleus localisation comment carrying only an **ECO:0000305 curator-inference** code rather than experimental evidence [E1]. In a 1,223-case international BCP-ALL transcriptome study, **four cases carried previously undescribed ZNF362 rearrangements - SMARCA2::ZNF362 (n = 3) and TAF15::ZNF362 (n = 1)** - which clustered inside the G5 subgroup otherwise defined by ZNF384 fusions, with the zinc-finger domains retained in both fusion proteins and JAK-STAT activation in both clusters; **the ZNF362 partners TAF15 and SMARCA2 also fuse to ZNF384, with similar breakpoints** [E2]. **Two uses for this graph.** First, ZNF362 fusions are the reason a ZNF384-signature case can be fusion-negative for ZNF384 - a diagnostic point Zaliova et al. make explicitly [E3]. Second, and more interesting, **ZNF362's six annotated fingers sit within six residues of ZNF384's first six and it has no counterpart to ZNF384's fingers at 403-425 and 433-455 - which is the most likely origin of the six-finger convention the leukaemia literature applies to ZNF384** [E1], see `ana-q173-the-znf384-zinc-finger-count-is-not-agreed`.
This is a prediction, not a measurement. No one has seen this protein in this shape. The colours say how much the software trusts itself, and that is worth reading before anything else — the orange stretches are places the model is effectively saying this part has no fixed shape.
I have never read one of these pictures before
A protein is one long chain of amino acids that folds up. The ribbon traces that chain from one end to the other; it is not a wire, it is a simplification of where the backbone runs. Drag to rotate, scroll to zoom.
Domains are the stretches of chain that do a particular job, and they are what the coloured blocks above the picture mark out. Click one and the view flies to it. In this project the important question about any domain is usually whether the fusion still has it — the labels say lost where it does not.
Anything in yellow sticks is a bound small molecule, which is usually the drug.
Why a four-case paralogue is worth an entry
ZNF362 fusions are a natural experiment that the field has not used. Verbatim from Li et al. 2:
"Four cases harbored previously undescribed ZNF362 rearrangements (n = 4), including SMARCA2-ZNF362 (n = 3) and TAF15-ZNF362 (n = 1). These cases clustered within the G5 subgroup, otherwise associated with ZNF384 fusions... Of note, the zinc-finger domains were retained in both fusion proteins, and both clusters showed similar gene expression profiles with activated JAK-STAT signaling pathway. Moreover, the fusion partners of ZNF362, namely TAF15 and SMARCA2, were also found to fuse to ZNF384, with similar breakpoints."
Same partners. Similar breakpoints. Same expression signature. Different index gene, with two fewer annotated zinc fingers and 157 fewer residues.
The inference that is available and has not been drawn: if a six-finger protein and an eight-finger protein, fused to the same partners at the same places, produce the same transcriptional output, then ZNF384's seventh and eighth fingers are not doing anything that distinguishes the subtype. That is a testable claim about the family's DNA-binding requirement, and the human data to support or refute it already exist in four patients.
The honest limits. n = 4, one cohort, expression clustering rather than occupancy, and the retention claim points to a supplementary figure this beat did not retrieve. The two proteins also differ in more than finger count - 420 versus 577 residues - so 'the extra fingers do not matter' is one of several readings.
The diagnostic consequence, which is immediate
Zaliova et al. set up their own study on exactly this point 3:
"In studies using the GEP to cluster B-other ALL, the ZNF384r cluster has often included cases without detectable ZNF384 rearrangement. In some of these 'ZNF384r-like' leukemias, rearrangement of ZNF362 (paralog of ZNF384) was identified. However, in some 'ZNF384r-like' cases, no established primary aberration has been found."
So a 'ZNF384-rearranged-like' case has at least three possible underlying lesions: a ZNF362 fusion, a noncanonical ZNF384 aberration such as a last-exon indel or an out-of-frame 5'-ZNF384 fusion (mechanism-znf384-c-terminal-truncation-phenocopies-the-fusion, fusion-znf384-tex41), or something still unidentified. A diagnostic workflow that tests only for ZNF384 fusions will call all three negative. Zaliova's recommendation - targeted manual reanalysis of ZNF384 and ZNF362 in any case with the signature and no detected fusion - is the operational consequence.
One inconsistency in the source, recorded rather than smoothed: Li et al.'s G5 summary table writes SMARCA2-ZNF362 (4), collapsing all four ZNF362 cases under the SMARCA2 label, while the body text gives SMARCA2 n = 3 and TAF15 n = 1. The body text is the more specific statement and is what this entry uses.
| uniprot | Q5T0B9 |
|---|---|
| length AA | 420 |
| alphafold ID | AF-Q5T0B9-F1 |
| hgnc symbol | ZNF362 |
| family | ZFAM4 / Kruppel C2H2-type zinc-finger family, paralogue of ZNF384 |
PDB IDS
[]
domains — the numbers behind the chart
[
{
"name": "ZF1 (C2H2 zinc finger)",
"start": 227,
"end": 249
},
{
"name": "ZF2 (C2H2 zinc finger)",
"start": 255,
"end": 277
},
{
"name": "ZF3 (C2H2 zinc finger)",
"start": 283,
"end": 305
},
{
"name": "ZF4 (C2H2 zinc finger)",
"start": 311,
"end": 335
},
{
"name": "ZF5 (C2H2 zinc finger)",
"start": 341,
"end": 363
},
{
"name": "ZF6 (C2H2 zinc finger)",
"start": 371,
"end": 393
}
]localization
{
"compartment": "nucleus",
"subnuclear": [],
"evidence_code": "ECO:0000305 - curator inference, NOT experimental. Per rule 91 this is weaker than the ECO:0000269 codes elsewhere in this corpus and should not be quoted as a measured localisation.",
"shown_for_fusion": "NO - no localisation experiment on any ZNF362 fusion protein was found"
}fusion partners reported
[ "SMARCA2 (n = 3)", "TAF15 (n = 1)" ]
measurements — the numbers behind the chart
[
{
"quantity": "length",
"subject": "ZNF362 Q5T0B9 canonical sequence",
"value": 420,
"units": "aa",
"n": 1,
"universe": "UniProtKB reviewed human entry; a gene_exact organism-restricted search returned exactly one record, so no symbol collision",
"null": 577,
"note": "the null is ZNF384's length - the paralogue is 157 residues shorter and lacks two annotated zinc fingers"
},
{
"quantity": "count",
"subject": "C2H2 zinc fingers annotated in ZNF362",
"value": 6,
"units": "domains",
"n": 1,
"universe": "UniProtKB Q5T0B9 feature table, spanning 227-393, retrieved 2026-09-24",
"null": 8,
"note": "the null is ZNF384's UniProt count. Six is also the number the leukaemia literature attributes to BOTH proteins, which is the observation ana-q173-the-znf384-zinc-finger-count-is-not-agreed is built on."
},
{
"quantity": "count",
"subject": "reported ZNF362 rearrangements in B-cell precursor ALL",
"value": 4,
"units": "patients",
"n": 1223,
"universe": "an international transcriptome study of 1,223 BCP-ALL cases; 0.33% of the cohort, all four inside the 74-case G5/ZNF384 cluster",
"null": 74,
"note": "the null is the size of the G5 cluster they sit inside - ZNF362 cases are about 5% of that cluster. A second cohort (158 B-other cases) looked specifically and found none."
}
]- This entry supports no intervention. Its one operational consequence is diagnostic and it cuts against a fusion-based enrolment rule: a ZNF384-signature patient may carry a ZNF362 fusion, a noncanonical ZNF384 lesion, or neither, and a trial selecting on 'ZNF384 fusion detected' excludes all of them while a trial selecting on the expression signature includes patients with no ZNF384 lesion for a ZNF384-directed agent to act on.
- Any therapeutic strategy aimed at the ZNF384 protein specifically - a degrader, a DNA-binding-surface ligand - would be expected to miss ZNF362-fusion patients entirely, since the target protein is a different gene product with 157 fewer residues, while those patients are clinically indistinguishable and sit in the same expression cluster.
- If a six-finger protein and an eight-finger protein, fused to the same partners at similar breakpoints, produce the same expression signature, do ZNF384's seventh and eighth fingers contribute anything? Four human cases already constitute the experiment; what is missing is an occupancy comparison. ZNF362-fusion CUT&RUN against the published 10,470-peak ZNF384-fusion reference set would answer it.
- Why is SMARCA2 the commonest ZNF362 partner (3 of 4) when it is a one-case rarity among ZNF384 partners? Either a real difference in partner preference between the paralogues, or noise at n = 4. If real, it is a clue about what each index gene needs from its partner.
- Is there a ZNF362 equivalent of the last-exon ZNF384 indel class? Nobody has looked. Zaliova et al. reanalysed ZNF362 reads in their three signature-positive cases and found nothing, which is a start at n = 3.
- Does ZNF362 bind the same [GC]AAAAA consensus as ZNF384? If the two paralogues have different DNA-binding preferences yet produce the same expression signature when fused, the signature is not simply a consequence of where the zinc fingers go - which would be a significant constraint on every mechanistic model in this family.
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
UniProtKB Q5T0B9 (ZN362_HUMAN, gene ZNF362, synonym PP6997) is a reviewed 420 aa human entry annotating exactly six C2H2-type zinc fingers, at 227-249, 255-277, 283-305, 311-335, 341-363 and 371-393, with disordered regions at 1-28, 54-80, 115-155 and 178-202 and a low-complexity compositional bias at 121-154; its function comment is 'May be involved in transcriptional regulation' and its nuclear localisation carries an ECO:0000305 curator-inference code, not experimental evidence. These six finger coordinates lie within six residues of ZNF384's first six (Q8TF68: 228-250, 256-278, 284-306, 317-339, 345-367, 373-397), and ZNF362 has no counterpart to ZNF384's fingers at 403-425 and 433-455.
UniProtKB entry Q5T0B9 (ZN362_HUMAN) feature table and comments, retrieved live 2026-09-24 by q173 and read out alongside Q8TF68 in the same session · UniProt Consortium 2026What this evidence cannot show
Both feature tables were fetched live in this session, not recalled; a reviewed organism-restricted gene_exact search for ZNF362 returned exactly ONE record, so there is no symbol collision here. THE COORDINATE COMPARISON IS NOT A SEQUENCE ALIGNMENT - no alignment was run and none is claimed; the two proteins differ in length by 157 residues, so near-identical coordinates in the 227-393 window are striking but do not by themselves establish one-to-one orthology of individual fingers. The function comment has no experimental evidence code at all, and per rule 91 the ECO:0000305 localisation call means curator inference rather than a read experiment.
Evidence that argues against this (1)
- Both records are annotated by the same profile detector, so a shared detector bias would affect both equally and the coordinate agreement could be an artefact of the method rather than of the proteins. The alternative reading of the whole comparison is also live: ZNF384's seventh and eighth fingers may be degenerate matches the detector over-calls, in which case ZNF362 is simply the cleaner protein and the paralogue similarity says nothing about the origin of the literature's six-finger convention. Distinguishing these requires a pairwise alignment, which was not run. UniProt Consortium 2026
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In an international transcriptome study of 1,223 BCP-ALL cases, four patients carried previously undescribed ZNF362 rearrangements - SMARCA2-ZNF362 (n = 3) and TAF15-ZNF362 (n = 1) - which clustered within the G5 subgroup otherwise associated with ZNF384 fusions; ZNF384 and ZNF362 are described as homologous C2H2-type zinc-finger transcription factors containing six zinc fingers in the ZFAM4 family, the zinc-finger domains were retained in both fusion proteins, both clusters showed similar gene expression profiles with activated JAK-STAT signalling, and the ZNF362 partners TAF15 and SMARCA2 were also found fused to ZNF384 with similar breakpoints. The G5 subgroup comprised 74 cases (6%) of the 1,223, with EP300-ZNF384 (53), TCF3-ZNF384 (12), TAF15-ZNF384 (11) and SMARCA2-ZNF362 (4).
Transcriptional landscape of B cell precursor acute lymphoblastic leukemia based on an international study of 1,223 cases. · Li JF, Dai YT, Lilljebjorn H, Shen SH, Cui BW, Bai L, et al. · Proc Natl Acad Sci U S A 2018What this evidence cannot show
FULL TEXT READ via the PMC HTML rendering of PMC6294900 (pnas.org returns 403). n = 4 ZNF362 cases, all in one study, and the authors themselves flag the group as small: 'The number of cases for some of the candidate leukemogenic abnormalities identified, such as ZNF362 fusions... was relatively small, which may explain the lack of detection of such cases in previous studies.' The zinc-finger retention claim points to SI Appendix Figure S8B, a supplementary schematic that was NOT retrieved. **THE PAPER CONTRADICTS ITSELF ON THE PARTNER SPLIT**: the G5 table row writes 'SMARCA2-ZNF362 (4)' while the body text says SMARCA2 n = 3 and TAF15 n = 1; the body text is used here.
Evidence that argues against this (1)
- A paper that disagrees with its own table on a partner count is not a strong authority for a descriptive claim it cites to a third source, and the six-zinc-finger statement is exactly that - referenced to the paper's reference 14, which this beat did not open. More substantively, 'clustered within the G5 subgroup' is expression clustering, not occupancy or function: four cases sitting inside a 74-case cluster is consistent with the ZNF362 fusions driving the same programme and equally consistent with them being a related but distinct entity that the clustering resolution cannot separate at n = 4. Zaliova M et al. 2021
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Cases with the ZNF384-rearranged gene-expression profile but no detectable ZNF384 rearrangement ('ZNF384r-like') include some with ZNF362 rearrangement and some with no established primary aberration; Zaliova et al. resolved two of the latter as last-exon ZNF384 indels and one as an out-of-frame ZNF384-TEX41 fusion, and recommend targeted reanalysis of ZNF384 and ZNF362 in any case with the signature and no detected fusion.
A novel class of ZNF384 aberrations in acute leukemia. · Zaliova M, Winkowska L, Stuchly J, Fiser K, Triska P, Zwyrtkova M, Hrusak O, Starkova J, Sramkova L, Stary J, Trka J, Zuna J · Blood Adv 2021What this evidence cannot show
FULL TEXT READ via Europe PMC fullTextXML for PMC8579251. The ZNF362 statement in this paper is a citation of Li et al. rather than an independent observation - Zaliova's own cohort contained no ZNF362 case, and their manual reanalysis of ZNF384 AND ZNF362 reads in their three signature-positive fusion-negative patients found no ZNF362 aberration. So this source establishes the diagnostic principle and adds no new ZNF362 cases.
Evidence that argues against this (1)
- Zaliova's own data are a partial negative for the ZNF362 explanation: they had three ZNF384r-like cases with no canonical fusion, they looked at ZNF362 specifically, and all three turned out to be ZNF384 lesions rather than ZNF362 fusions. With four ZNF362 cases reported in 1,223 patients in one study and zero in a 158-case B-other cohort that looked, the ZNF362 route may be considerably rarer than the noncanonical-ZNF384 route - which inverts the emphasis a reader would take from the literature, where ZNF362 is the named explanation and the ZNF384 indels are newer. Li JF et al. 2018
- analogous to →ZNF384 - a C2H2 transcription factor that is the invariant 3' half of a whole B-ALL fusion subtype, including AKAP8::ZNF384
paralogue; ZNF362 fusions produce the same expression signature and share the partners TAF15 and SMARCA2 with similar breakpoints
ZNF362 has exactly six UniProt C2H2 fingers, within 6 residues of ZNF384's first six - the likely origin of the literature's six-finger convention