Six-pass transmembrane protein of the trans-Golgi network, encoded at Xq28 and formerly known as CXorf12 or ITBA1. It is ubiquitously expressed, has no recognisable catalytic, transport or adaptor domain, and defines a protein family of its own (Pfam PF15100). TMEM187 binds the small GTPase RAB11A, preferentially in its GDP-bound form, and acts as a negative regulator of endosomal recycling: in its presence RAB11A is less available to its guanine-nucleotide exchange factor GRAB, recycling of transferrin receptor 1 back to the plasma membrane is slowed, and cellular iron uptake is held down. In erythroid cells this sets a brake on differentiation. Loss of TMEM187 in human erythroleukaemia lines accelerates iron uptake and triggers erythroid differentiation without inducing agents, leading to premature maturation with phosphatidylserine exposure, membrane fragility and increased macrophage clearance; zebrafish lacking tmem187 show enhanced early erythropoiesis, and forced expression of human TMEM187 in mouse haematopoietic stem cells, in an organism with no endogenous orthologue, compromises erythropoiesis and produces moderate anaemia. The molecular activity through which TMEM187 achieves this is not established: binding to RAB11A is demonstrated, but whether it acts by occluding the GEF, by sequestering RAB11A in a membrane subdomain, or by some other means has not been determined.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0030133 transport vesicle | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assertion of a vesicular localisation, consistent with the trans-Golgi network localisation reported experimentally in 2026. Reason: Correct in kind. The WITH/FROM for this row is PANTHER:PTN001030718 plus UniProtKB:Q14656, that is, the node was seeded by this gene's own IDA - which is the expected pattern when a family has one experimentally characterised member, not a circularity. Since PANTHER PTHR15066 contains essentially only TMEM187 orthologues, the IBA adds the statement that the localisation is ancestral rather than human-specific. Accepted rather than modified: the more precise compartment, trans-Golgi network (GO:0005802), is proposed as an addition below rather than as a replacement, because vesicular and TGN localisation are both reported and the 2026 study describes TMEM187 acting on vesicle release from the Golgi. |
| GO:0016020 membrane | IEA GO_REF:0000044 | MODIFY | Summary: Correct - TMEM187 is a multi-pass membrane protein - but maximally general, and the specific membrane is now known. Reason: UniProt could only say 'Membrane; Multi-pass membrane protein' by prediction (ECO:0000305). The 2026 study localises TMEM187 primarily to the trans-Golgi network, so the trans-Golgi network membrane term captures the same fact with real information content. Proposed replacements: trans-Golgi network membrane Supporting Evidence: PMID:41824385 We found that TMEM187, primarily localized to the trans-Golgi network, interacts with RAB11A |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Bare protein binding from the HuRI binary interactome map. Until 2026 this was the entirety of TMEM187's molecular-function record. Reason: Carries no functional information. The informative interaction for this protein is with RAB11A, which is proposed below as small GTPase binding; the high-throughput binary partners recorded here have not been connected to any function. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0030133 transport vesicle | IDA GO_REF:0000054 | ACCEPT | Summary: Localisation of a GFP-tagged fusion protein in living cells, from the LIFEdb high-throughput localisation project. Reason: Consistent with the trans-Golgi network localisation reported in 2026, and it is the observation that seeded the corresponding IBA. Accepted, with the caveat that it derives from an overexpressed tagged construct in a high-throughput screen rather than from detection of the endogenous protein. |
| GO:0031267 small GTPase binding | IPI PMID:41824385 TMEM187 is a novel brakelike modulator in the regulation of ... | NEW | Summary: Proposed addition, and the informative replacement for the bare protein binding row: TMEM187 co-immunoprecipitates with RAB11A, with a preference for the GDP-bound state. Reason: Demonstrated by reciprocal co-immunoprecipitation in two cell backgrounds (EGFP-RAB11A with HA-TMEM187 in HEK293, 3xFLAG-RAB11A with HA-TMEM187 in K562) and supported by colocalisation, with nucleotide-state selectivity established using the GDP-locked S25N mutant. This is a binding assertion and is deliberately not promoted to the core molecular function: what TMEM187 does to RAB11A once bound is not established. Supporting Evidence: PMID:41824385 Mechanistically, we demonstrate that TMEM187 interacts with RAB11A to restrain endosomal recycling by interfering with RAB11A-GRAB association, involved with endosomal vesicle back to the plasma membrane, that activates RAB11A. PMID:41824385 Interestingly, we found that TMEM187 preferentially interacts with GDP-bound RAB11A (S25N). |
| GO:0005802 trans-Golgi network | IDA PMID:41824385 TMEM187 is a novel brakelike modulator in the regulation of ... | NEW | Summary: Proposed addition. The specific compartment TMEM187 occupies, replacing the inference-only 'Membrane' statement that UniProt currently carries. Reason: Directly observed by fluorescence microscopy of TMEM187-EGFP against Golgi and RAB11A markers, and the compartment the mechanism requires - RAB11A itself resides at the trans-Golgi network, recycling endosomes and secretory vesicles. Supporting Evidence: PMID:41824385 We found that TMEM187, primarily localized to the trans-Golgi network, interacts with RAB11A PMID:41824385 Here, we identify human TMEM187, a Golgi transmembrane protein of unknown function, as a novel negative regulator of erythropoiesis. |
| GO:0001920 negative regulation of receptor recycling | IMP PMID:41824385 TMEM187 is a novel brakelike modulator in the regulation of ... | NEW | Summary: Proposed addition. TMEM187 slows the return of transferrin receptor 1 to the plasma membrane; its loss increases surface TfR1 and transferrin uptake. Reason: The most specific process term that the data support. In TMEM187 knockout K562 cells, TfR1 levels rise and shift to the plasma membrane, holo-transferrin uptake increases before and after erythroid induction, and GRAB colocalisation with TfR1 increases - all consistent with release of a brake on RAB11A-dependent recycling. This is a process claim, not a mechanism claim; the molecular step by which TMEM187 imposes the brake is left unasserted. Supporting Evidence: PMID:41824385 Consequently, TMEM187 modulates TfR1 recycling to the cell membrane to fine-tune iron uptake efficiency for erythropoiesis. PMID:41824385 Lack of TMEM187 in cell models initiates erythropoiesis without the normal induction protocol and accelerates iron uptake. |
| GO:0045647 negative regulation of erythrocyte differentiation | IMP PMID:41824385 TMEM187 is a novel brakelike modulator in the regulation of ... | NEW | Summary: Proposed addition. TMEM187 restrains erythroid differentiation and maturation; this is the organismal role the paper is built around. Reason: Supported by loss of function and gain of function in three systems and in both directions: knockout human erythroleukaemia cells differentiate without induction and mature prematurely; tmem187-deleted zebrafish show enhanced early erythropoiesis; and expression of human TMEM187 in mouse haematopoietic stem cells - a particularly clean test, because mice carry no endogenous orthologue - compromises erythropoiesis and causes moderate anaemia. Supporting Evidence: PMID:41824385 Together, we have demonstrated that TMEM187 acts as a novel negative regulator of erythroid differentiation and maturation. PMID:41824385 whereas hematopoietic stem cell expression of human TMEM187 in mice, which lack a homologous gene endogenously, results in compromised erythropoiesis and moderate anemia PMID:41824385 In zebrafish embryos, tmem187 deletion leads to enhanced early erythropoiesis, although this phenotype is later compensated |
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Download this section (compressed HTML)Q: Does TMEM187 inhibit GRAB-catalysed nucleotide exchange on RAB11A directly, or does it restrain recycling some other way? This is the single experiment that would convert TMEM187's GO molecular function from a binding term into an activity. The competition model currently rests on co-immunoprecipitation, colocalisation and expression changes, not on a measured exchange rate.
Suggested experts: Kai Li, Yang Liu
Q: Is the observed preference of TMEM187 for GDP-bound RAB11A (S25N) reconcilable with the reported behaviour of GRAB? The authors note that their nucleotide-state preference for GRAB is the opposite of what earlier axon-outgrowth studies found, which matters because the whole competition model depends on both proteins contending for the same RAB11A conformer.
Suggested experts: Kai Li
Q: Should any molecular-function term be asserted for TMEM187 at this stage, or is small GTPase binding (GO:0031267) the correct ceiling? The cellular component and biological process are now reasonably clear, which creates pressure to supply a matching MF - but adaptor, cargo receptor and transporter are all unsupported.
Q: Does TMEM187 act outside the erythroid lineage? It is ubiquitously expressed and X-linked, yet mice have lost the gene entirely and all functional data come from erythroid systems.
Suggested experts: Kai Li, Yvette Y Yien
Experiment: Purify RAB11A and the GRAB (RAB3IL1) GEF domain, and reconstitute TMEM187 into detergent micelles or nanodiscs. Measure GDP release and GTP loading on RAB11A (mant-nucleotide fluorescence or filter-binding) with and without TMEM187, over a TMEM187 concentration series, and test whether a TMEM187 mutant that fails to co-immunoprecipitate RAB11A also fails to inhibit exchange.
Hypothesis: TMEM187 restrains RAB11A activation by occluding the surface that its GEF GRAB engages, so TMEM187 should slow GRAB-catalysed GDP release from RAB11A in a reconstituted system.
Type: Reconstituted guanine-nucleotide exchange assay
Experiment: Perform proximity-dependent biotinylation from TMEM187 in K562 cells before and after erythroid induction and ask whether TfR1 or other recycling cargoes appear in the proximitome; in parallel, test whether the TfR1 surface phenotype of TMEM187 knockout cells is abolished by a RAB11A mutant locked in the GDP state. If cargo never appears and the RAB11A epistasis is complete, the adaptor and cargo-receptor hypotheses can be formally excluded rather than merely left unasserted.
Hypothesis: TMEM187's effect on TfR1 is entirely indirect, via RAB11A, with no TMEM187-cargo contact.
Type: Proximity labelling plus epistasis with RAB11A nucleotide-state mutants
Experiment: Reconstitute purified TMEM187 into proteoliposomes and screen for transport or conductance using a broad panel (ions including iron species, protons, small metabolites) with electrophysiology and radiotracer flux. A clean negative result across a wide panel would be worth publishing, because it would justify treating the transmembrane region as structural and redirect effort to the cytosolic surfaces that contact RAB11A.
Hypothesis: The six transmembrane helices are functional rather than merely anchoring, and TMEM187 may move a substrate across the TGN membrane.
Type: Proteoliposome transport and conductance screen
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