Annotation inferences using phylogenetic trees
Mutation of FKBP associated protein 48 (FAP48) at proline 219 disrupts the interaction with FKBP12 and FKBP52.
Ligand-regulated binding of FAP68 to the hepatocyte growth factor receptor.
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Glomulin/FAP68 (isoform 1) binds the C-terminal tail of the inactive (unphosphorylated/kinase-defective) MET receptor, is released upon MET phosphorylation, and free FAP68 stimulates the downstream kinase p70 S6 kinase.
Mutations in a novel factor, glomulin, are responsible for glomuvenous malformations ("glomangiomas").
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Loss-of-function germline (and somatic second-hit) mutations in GLMN cause glomuvenous malformations, vascular lesions with abnormal smooth-muscle-like glomus cells, implicating glomulin in vascular smooth-muscle cell differentiation and vascular morphogenesis.
The FKBP-associated protein FAP48 is an antiproliferative molecule and a player in T cell activation that increases IL2 synthesis.
The glomuvenous malformation protein Glomulin binds Rbx1 and regulates cullin RING ligase-mediated turnover of Fbw7.
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Glomulin binds directly to the RING domain of RBX1 and inhibits its E3 ubiquitin ligase activity; glomulin loss decreases FBXW7 (Fbw7) levels and increases Cyclin E and c-Myc, with the increased FBXW7 turnover dependent on CRL and proteasome activity, demonstrating that glomulin modulates CRL1(Fbw7) E3 activity.
A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways.
A reference map of the human binary protein interactome.
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
FAP48, a new protein that forms specific complexes with both immunophilins FKBP59 and FKBP12. Prevention by the immunosuppressant drugs FK506 and rapamycin.
Falcon deep research report for human GLMN
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Glomulin is a non-enzymatic, high-affinity inhibitor of RBX1-containing cullin-RING ligases (Kd ~38.6 nM), binding the RBX1 RING domain via a minimal region (residues ~300-594) and masking the E2-binding surface to outcompete the E2 enzyme CDC34 and block ubiquitin chain synthesis.
"GLMN binds RBX1 with **high affinity** (reported Kd ~**38.6 nM**) and a minimal RBX1-binding GLMN region mapped to residues **300–594**. (duda2012structureofa pages 7-9) - GLMN **masks the E2-binding site** on RBX1, thereby **outcompeting** the E2 enzyme **CDC34** and **inhibiting ubiquitin chain synthesis** by neddylated CUL1–RBX1 and SCF complexes."
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Glomulin is selective for RBX1 over RBX2 and associates with CUL1-containing SCF/CRL1 complexes and other cullins, with the best-supported pathway being CRL/SCF regulation, especially CRL1/SCF(FBW7).
"GLMN interacts selectively with **RBX1** and shows little/no interaction with **RBX2** in the cited biochemical/cell-based experiments."
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Beyond CRL regulation, glomulin binds the RING domains of cIAP1 and cIAP2, inhibits their self-ubiquitination, and acts as a negative regulator of cIAP-mediated inflammasome activation and macrophage pyroptosis; the Shigella effector IpaH7.8 ubiquitinates and degrades glomulin to enhance inflammation.
"GLMN binds **cIAP1 and cIAP2** via their **RING domains** and inhibits their **self-ubiquitination**. (suzuki2018shigellahijacksthe pages 1-2) - Modulating GLMN levels altered inflammasome responses; the authors conclude GLMN is a **negative regulator of cIAP-mediated inflammasome activation**."
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Glomulin shows stimulus-dependent localization near inflammasome structures, forming puncta that colocalize with active caspase-1 after LPS/ATP stimulation in macrophages.
"Upon LPS/ATP stimulation, **GLMN forms puncta that colocalize with active caspase-1**, and GLMN can colocalize with cIAP2 after Shigella infection, supporting a stimulus-dependent localization near inflammasome-associated structures."