Where wild-type PICALM actually is: coated pits, the Golgi, coated vesicles - and a nuclear pool nobody has explained
also called PICALM subcellular localization
The normal PICALM protein sits mostly at the cell surface where it helps build the cages that pull things into the cell, and also around the Golgi. A smaller amount goes into the nucleus, and nobody knows what it does there.
The same thing, for a scientist
UniProt annotates Q13492 to **cell membrane; membrane, clathrin-coated pit; Golgi apparatus; cytoplasmic vesicle, clathrin-coated vesicle; and nucleus**, with experimental evidence codes on each, the coated-pit/Golgi/vesicle set traced to the founding localisation study and the nuclear annotation traced to PIMREG-dependent nuclear targeting [E1][E2]. Functionally the membrane pool is the one with mechanism: CALM senses and drives membrane curvature and thereby sets coated-vesicle size and maturation [E3], and in erythroblasts it is required for transferrin-receptor internalisation and for efficient clathrin coat maturation as seen by freeze-etch electron microscopy [E4]. **The nuclear pool has no assigned function**, and endocytic proteins as a class shuttle [E2]. That unexplained pool is exactly the compartment the leukaemic fusion lives in and out of, which makes 'what is PICALM doing in the nucleus' a question with a clinical edge rather than a curiosity.
Compartment-by-compartment, with what each rests on
| compartment | evidence | strength |
|---|---|---|
| clathrin-coated pit (plasma membrane) | immunofluorescence and clathrin binding in cultured cells 1 | established |
| Golgi area | colocalisation with clathrin 1 | established |
| clathrin-coated vesicle | same study 1 | established |
| cell membrane generally | curvature sensing and driving; coat maturation 34 | strong |
| nucleus | UniProt experimental annotation, PIMREG interaction proposed to target PICALM there 2 | moderate, and unexplained |
No subnuclear localisation has been reported. Whether the nuclear pool is diffuse, at speckles, at the lamina or at specific loci is, as of 2026-09-20, unaddressed - which matters because this graph maintains a whole subnuclear layer for KMT2A fusions and has no counterpart here.
| mechanism class | subcellular localization |
|---|---|
| subnuclear localization | not reported as of 2026-09-20 |
| nuclear targeting partner | PIMREG |
| why it matters here | The unexplained nuclear pool is the compartment the leukaemic fusion cycles through, and the fusion's only essential element from PICALM is a nuclear export signal. |
compartments
[ "cell membrane", "clathrin-coated pit", "Golgi apparatus", "clathrin-coated vesicle", "nucleus" ]
cell types with resolved function
[ "erythroblast (transferrin-receptor uptake, coat maturation)", "murine embryonic fibroblast (TfR internalisation)" ]
cell types where dispensable
[ "myeloid progenitors", "B-lymphoid progenitors" ]
- Localisation annotations here come mostly from overexpression in non-haematopoietic cells; the endogenous distribution in a leukaemic blast is unmeasured.
- An intervention aimed at the membrane pool would hit the erythroid requirement, which is the one compartment where PICALM is genuinely essential in vivo.
- What is PICALM doing in the nucleus? No function has been assigned and no subnuclear compartment has been reported.
- Is the nuclear pool present in haematopoietic cells, or only in the cell types where PIMREG is expressed? The annotation says 'in some cells' and nobody has enumerated which.
- Does the wild-type allele's nuclear pool interact with the fusion? Two proteins sharing a compartment and a CRM1 dependency is the setting for a dominant-negative interaction nobody has looked for.
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
CALM localises to endocytic coated pits and colocalises with clathrin in the Golgi area; it binds clathrin, and overexpression perturbs clathrin-mediated traffic.
Clathrin assembly lymphoid myeloid leukemia (CALM) protein: localization in endocytic-coated pits, interactions with clathrin, and the impact of overexpression on clathrin-mediated traffic. · Tebar F, et al. · Mol Biol Cell 1999What this evidence cannot show
Immunofluorescence and overexpression in cultured non-haematopoietic cells. This is the study UniProt cites for the coated-pit, Golgi and coated-vesicle annotations.
Evidence that argues against this (1)
- The coated-pit localisation was established by overexpression in cultured non-haematopoietic cells and implies a general endocytic requirement that the mouse genetics contradicts: Picalm is dispensable for myeloid and B-lymphoid development and its requirement is erythroid-restricted. Ishikawa Y et al. 2015
- E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
UniProt Q13492 carries experimental subcellular-location annotations for cell membrane, clathrin-coated pit, Golgi apparatus, clathrin-coated vesicle and nucleus, with the nuclear annotation attributed to PIMREG interaction targeting PICALM to the nucleus in some cells.
UniProtKB Q13492 (PICAL_HUMAN) - subcellular location annotations with evidence codes · UniProt Consortium 2026What this evidence cannot show
Fetched live 2026-09-20. A curated annotation is a pointer to primary evidence, not primary evidence; the nuclear annotation rests on a single interaction study and 'in some cells' is doing real work in that sentence.
Evidence that argues against this (1)
- PUBLISHED RESULT THAT REFRAMES THE ANNOTATION, and it changes 'a nuclear pool nobody has explained' into something narrower. The interaction the curated nuclear annotation rests on has been followed up, and the causal direction is the reverse of a resident pool: the partner is itself nuclear with a preference for nucleoli, and it is EXPRESSION OF THE PARTNER that markedly increases the nuclear localisation of CALM. Its levels are cell-cycle dependent and mitogen-induced, so the nuclear fraction of PICALM is a conditional, proliferation-linked state rather than a steady-state compartment. 'In some cells' in the UniProt annotation is doing exactly this work, and the entry should say which cells and when rather than treat the pool as unexplained. Archangelo LF et al. 2006
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
CALM regulates clathrin-coated-vesicle size and maturation by directly sensing and driving membrane curvature.
CALM regulates clathrin-coated vesicle size and maturation by directly sensing and driving membrane curvature. · Miller SE, et al. · Dev Cell 2015What this evidence cannot show
Largely isolated-ANTH-domain constructs and reconstituted membranes; the structures underpinning it are rat.
Evidence that argues against this (1)
- PUBLISHED CONFLICTING RESULT: a general biophysical mechanism does not predict the lineage-restricted requirement that is observed in vivo. Curvature sensing by the ANTH domain is a property every cell's CALM should have, yet mouse genetics puts the requirement in one compartment - Picalm is required for efficient clathrin coat maturation and transferrin-receptor endocytosis in ERYTHROBLASTS and is essential for erythroid development, while being dispensable for myeloid and B-lymphoid development. Either the curvature function is redundant in most lineages, or the reconstituted assay is not measuring the step that limits coat maturation in cells. The in vitro mechanism and the in vivo requirement have never been reconciled. Ishikawa Y et al. 2015
- E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Freeze-etch electron microscopy of primary erythroblasts and live-cell imaging of MEFs show that Picalm function is required for efficient clathrin coat maturation, and the PIP2-binding domain is necessary for transferrin-receptor endocytosis in erythroblasts and essential for erythroid development.
Role of the clathrin adaptor PICALM in normal hematopoiesis and polycythemia vera pathophysiology. · Ishikawa Y, et al. · Haematologica 2015What this evidence cannot show
Mouse. This is the strongest cell-type-resolved localisation-to-function link available for PICALM and it is erythroid, not lymphoid or myeloid.
Evidence that argues against this (1)
- PUBLISHED CONFLICTING RESULT that loosens the attribution to endocytosis. The erythroid phenotype is read here as a transferrin-receptor-endocytosis requirement, but PICALM level has at least one non-endocytic downstream consequence in the same direction: modulating PICALM levels perturbs cellular CHOLESTEROL homeostasis. Erythroid membranes are unusually cholesterol-dependent, so a lineage-restricted phenotype under PICALM loss is consistent with a lipid-handling defect as well as with an iron-uptake defect, and the mouse experiment does not separate them. 'The compartment that needs PICALM most is the erythron' is safe; 'because of transferrin-receptor endocytosis' is the part that is not isolated. Mercer JL et al. 2015
where the wild-type protein is
the fusion inherits the 5' partner's cytoplasmic bias and its shuttling
the membrane pool whose function is lost
PICALM's own subcellular record: fully ECO:0000269-coded across five compartments, nuclear pool included
The same question as PICALM's and with a sharper structural answer: USP8's endosomal-localisation signal is the N-terminal MIT domain (PMID 17711858), which is NOT retained in KMT2A::USP8, while KMT2A's CxxC and AT-hooks are. Wild-type USP8 compartment data therefore cannot be transferred to the fusion - the fusion is predicted nuclear with an endosomal enzyme's substrate preference (Q95 2026-09-22)