- Fold
- Soluble, single-chain protein; predicted trypsin-like serine-protease fold; no transmembrane segments.
- Active Site
- The UniProt-annotated His490–Asp544–Ser650 charge-relay triad — the functional site. AstraBIND's retrieval-based detector found no ligand-bound relative and did not recover it, so we defer to the annotation (a useful negative control).
- Clean Signal
- No amyloidogenic segments predicted — a clean aggregation profile for construct design.
Model-reported confidence for the headline calls (amber = the load-bearing prediction the rest of the profile builds on). These are model-estimated probabilities that rank and gate each call — not calibrated rates of experimental success.
The Gap
Why This Target Is Still Dark
Most tractable protein families have been structurally explored; FAM111B has not. It is an IDG Tbio serine protease with no experimental structure in the PDB and a thin primary literature. What makes the gap matter is the biology on either side of it: dominant FAM111B mutations cause POIKTMP — hereditary fibrosing poikiloderma with tendon contractures, myopathy and progressive pulmonary fibrosis — while in oncology it has been reported as a direct p53 target that drives lung adenocarcinoma. A disease gene and a candidate oncology target, and still no fold to reason over.
That combination — genuine disease relevance, near-zero structural information — is where prediction earns its keep: everything below is computed from the canonical 734-residue sequence with Orbion's Astra suite, with no experimental FAM111B structure used as input. For a genuine orphan, there is nothing to look up.
Architecture & Topology
How the Sequence Is Organised
| Element | Residues | Note |
|---|---|---|
| Chain | 1–734 | Single-chain; see disorder profile and pocket below. |
The Predicted Pocket
The Annotated Catalytic Triad
For FAM111B the functional site is annotated, not predicted: UniProt places a His490–Asp544–Ser650 charge-relay triad. This target is also a useful negative control for the pocket detector — AstraBIND had no ligand-bound relative to retrieve from and returned a surface that does not overlap the triad, so we report the annotated active site rather than an invented pocket. Protease activity itself is a sequence-based inference, not experimentally confirmed here.
Site: Trypsin-like serine-protease charge-relay triad (UniProt)
Post-Translational & Structural Features
Specific, Testable Residues
- Catalytic residue Charge relay system (position 490). UniProt-annotated active site — one of three charge-relay residues that together form the His–Asp–Ser catalytic triad of a trypsin-like serine protease.
- Catalytic residue Charge relay system (position 544). UniProt-annotated active site — the second member of the predicted triad; the geometry of all three is what a structure would need to confirm.
- Catalytic residue Charge relay system (position 650). UniProt-annotated active site — the third triad residue; the trio (490 / 544 / 650) is the signature that classes FAM111B as a serine protease.
- No amyloidogenic segments predicted. AstraUNFOLD flags no aggregation-prone stretch — a clean profile for recombinant expression and construct design.
Recommended Experimental Follow-Up
An Orphan Sequence, Turned Into a Ranked Plan
Each prediction is paired with the experiment that would test it and the readout to watch for.
| Prediction | Experiment | Readout |
|---|---|---|
| Unknown physiological substrate(s) | Activity-based protein profiling / N-terminomics in FAM111B-active cells | Identify the cleaved substrates that define its pathway |
| Catalytic Triad (charge Relay 490 / 544 / 650) | Serine → alanine active-site mutant + protease-activity assay | Loss of proteolysis — confirms the serine-protease call |
| Disordered Termini (1–32, 712–734) | N- and C-terminal truncation to the folded core | Improved expression and amenability to crystallography / cryo-EM |
Scope & Limitations
What This Is — and Isn't
- Prediction, not experiment. These are computational hypotheses to prioritise experiments — not a structure or an assay. Nothing here is wet-lab validated.
- The pocket is predicted; the ligand is not named. AstraBIND is retrieval-based; the honest output is a residue-level hypothesis, not a proven druggable site or a validated binder.
- The enzyme call is itself an inference. FAM111B is annotated as a serine protease with a His–Asp–Ser charge-relay triad, but its physiological substrates are unknown, and the links to POIKTMP and to lung adenocarcinoma rest on genetics and expression studies rather than a worked-out mechanism. Treat both the protease identity and the disease rationale as hypotheses.
All predictions were generated with Orbion's Astra suite from the canonical FAM111B sequence (UniProt Q6SJ93), using AlphaFold-derived structural features. Reported values are model outputs; model internals are out of scope.
References
- [1]UniProt Consortium. UniProtKB entry Q6SJ93 (FAM111B, human). uniprot.org.
- [2]Pharos (Illuminating the Druggable Genome). FAM111B target record — Tbio. pharos.nih.gov.
- [3]Mercier S et al. Mutations in FAM111B cause hereditary fibrosing poikiloderma with tendon contracture, myopathy, and pulmonary fibrosis. (2013). https://doi.org/10.1016/j.ajhg.2013.10.013
- [4]Sun H et al. FAM111B, a direct target of p53, promotes the malignant process of lung adenocarcinoma. (2019). https://doi.org/10.2147/ott.s190934
- [5]Kawasaki K et al. FAM111B enhances proliferation of KRAS-driven lung adenocarcinoma by degrading p16. (2020). https://doi.org/10.1111/cas.14483