FYRN/FYRC: the clip that holds the cut reciprocal protein together, and the only fusion-adjacent interface anyone has tried to break with a decoy
also called FYRN-FYRC heterodimerisation · AF4-MLL heterodimer interface · MLL FYR domains
After the cut, the two halves of the mirror-image fusion protein do not drift apart - a pair of matching surfaces clips them back together. Blocking that clip with a decoy piece destroys the whole oncoprotein in a dish.
The same thing, for a scientist
FYRN (KMT2A 2018-2074) and FYRC (KMT2A 3666-3747) are the reciprocal pair of interaction domains that re-associate the two Taspase1 cleavage products [E2]. In AFF1::KMT2A both are retained, on opposite sides of the cleavage sites, so the mature oncoprotein is an AF4-MLL-N / MLL-C heterodimer [E1]. The minimal interaction interface was mapped in a bacterial two-hybrid system and confirmed with a mammalian biosensor, and expression of FYRC or smaller fragments of it blocked heterodimer formation, prevented high-molecular-weight complex assembly and destroyed the AF4-MLL oncoprotein [E1]. This is the only interface on any KMT2A reciprocal product for which a deliberate disruption experiment has been published. Its problem is selectivity: the identical FYRN/FYRC pair is present on wild-type KMT2A [E2], and the same interface governs the wild-type MLL-N/MLL-C heterodimer, so a decoy has no way to discriminate.
Where the interface sits relative to the cut
Why the decoy result is real and still not a drug
The experiment is clean in its own frame: a defined minimal interface, two orthogonal assays, and a construct that abolishes complex formation and destroys the oncoprotein 1. What is missing is everything that would make it translatable - it was done on over-expressed protein, not on an endogenous fusion in a patient-derived line; no leukaemia model was treated; and the interface is shared with wild-type KMT2A, whose own heterodimer the decoy would also break. A peptide or small molecule against FYRN/FYRC is, by construction, a pan-KMT2A agent.
| partner a | protein-aff1-kmt2a-reciprocal-product |
|---|---|
| partner b | gene-kmt2a |
| motif a | FYRN (KMT2A 2018-2074) |
| motif b | FYRC (KMT2A 3666-3747) |
| druggability | A protein-fragment decoy works in over-expression assays; the interface is shared with wild-type KMT2A, so no selectivity is available from the target itself. No structure of the FYRN/FYRC complex has been deposited. |
interface residues a
[ 2018, 2074 ]
interface residues b
[ 3666, 3747 ]
structures
[]
ligands
[]
- The interface is identical on wild-type KMT2A, so any agent against it is a pan-KMT2A agent and inherits KMT2A's haploinsufficiency phenotype as a toxicity prior.
- The decoy experiment destroys an over-expressed oncoprotein; the one experiment that removed the endogenous reciprocal transcript from t(4;11) cells found no phenotype at all.
- A protein-fragment decoy is not a deliverable modality in an infant leukaemia, and no peptidomimetic or small molecule against FYRN/FYRC has been reported.
- Is there any structure of the FYRN/FYRC complex? None was found for this beat, and without one a small-molecule campaign has no starting point.
- Does a FYRC decoy affect wild-type KMT2A function measurably, or is the fusion heterodimer somehow more dependent on the interface?
- Would breaking the heterodimer in an established t(4;11) line do anything, given that siRNA against the reciprocal transcript in the same lines did nothing?
- E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
The AF4-MLL oncoprotein is activated by Taspase1 hydrolysis into AF4-MLL-N and MLL-C fragments that heterodimerise through FYRN and FYRC; the minimal interaction interface was defined in a bacterial two-hybrid system and a mammalian biosensor assay, and expression of the FYRC domain or smaller portions blocked heterodimer formation, blocked multiprotein complex assembly and destroyed the AF4-MLL oncoprotein.
The heterodimerization domains of MLL-FYRN and FYRC--are potential target structures in t(4;11) leukemia. · Pless B, Oehm C, Knauer S, et al. · Leukemia 2011What this evidence cannot show
Over-expression systems throughout; no endogenous fusion, no patient-derived line, no in vivo model, and the decoy is a protein fragment rather than a deliverable modality. The same group produced the model in which the reciprocal product is leukaemogenic, so the choice of target is not independent of that position.
Evidence that argues against this (1)
- Whether destroying AF4-MLL would do anything in an established t(4;11) leukaemia is directly contradicted by siRNA knockdown of AF4-MLL in RS4;11 and SEMK2-M1, which had no effect on growth, cell cycle or apoptosis. Kumar AR et al. 2011
- E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
UniProt Q03164 annotates FYR N-terminal at 2018-2074 and FYR C-terminal at 3666-3747 on wild-type KMT2A, with Taspase1 cleavage sites at 2666/2667 and 2718/2719 lying between them.
UniProt Q03164 (KMT2A_HUMAN), feature table · UniProt Consortium · UniProtKB 2026What this evidence cannot show
Fetched from the UniProt REST record 2026-09-19 with the primary gene name read back as KMT2A. UniProt annotates the domains; it does not state that they mediate the post-cleavage heterodimer, which comes from the experimental literature.
Evidence that argues against this (1)
- Because these coordinates are wild-type KMT2A coordinates, they establish that any FYRN/FYRC-directed agent engages the normal protein as well as the fusion; the same domains govern the wild-type MLL-N/MLL-C heterodimer. Sabiani S et al. 2015
The interface that re-associates the two Taspase1 cleavage products of the reciprocal oncoprotein.
- part of →KMT2A / MLL1 — the gene that breaks
FYRN 2018-2074 and FYRC 3666-3747 are wild-type KMT2A domains, which is why a decoy cannot be fusion-selective.
Cleavage creates the two fragments that the FYRN/FYRC interface then re-associates.