- Fold
- Predicted single-pass membrane protein: a signal peptide, a folded extracellular domain, one transmembrane helix and a long, largely disordered cytoplasmic tail.
- Binding Pocket
- A residue-level surface-cavity hypothesis from AstraBIND (confidence 0.819) in the extracellular domain — a starting point for docking or mutagenesis, not a validated ligand.
- Structural Anchors
- N-linked glycosylation at N66, N201, N221 and N265 (UniProt), all on the extracellular domain.
- Flexible Regions
- Elevated predicted disorder through the long cytoplasmic tail, strongest at the C-terminus (801–817) — natural construct / truncation boundaries.
- Clean Signal
- No amyloidogenic segments predicted — a clean aggregation profile despite the large disordered region.
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; FAM171A2 has not. It is IDG Tdark in the fullest sense — no experimental structure in the PDB, no UniProt function summary, and only a handful of papers to its name. What lifted it out of obscurity is disease genetics: it was reported first as a regulator of progranulin expression that modifies risk across several neurodegenerative diseases, and then as a neuronal mediator of α-synuclein fibril uptake that drives Parkinson's disease. A candidate node in α-synuclein spread, with almost nothing structural to anchor it.
That combination — a credible neurodegeneration link, near-zero structural information — is where prediction earns its keep: everything below is computed from the canonical 826-residue sequence with Orbion's Astra suite, with no experimental FAM171A2 structure used as input. For a genuine orphan, there is nothing to look up.
Architecture & Topology
How the Sequence Is Organised
| Element | Residues | Note |
|---|---|---|
| Transmembrane Helices | 1 predicted | Boundaries: 316–336. |
| Signal Peptide | 1–29 | UniProt. |
The Predicted Pocket
A Predicted Binding Pocket
For this genuine orphan, AstraBIND has no ligand-bound relative to retrieve from — so these residues are a structure-based cavity prediction, not a retrieval-grounded pocket, and the score reflects cavity geometry rather than a known binding site. Treat them as an exploratory starting point for mutagenesis only; the topology, disorder and modification maps above are the higher-confidence outputs for this target. No validated ligand; not a proven druggable site.
Site: Predicted surface cavity
Post-Translational & Structural Features
Specific, Testable Residues
- N-glycosylation at position 66, 201, 221, 265 (UniProt) — four N-linked sequons clustered on the extracellular domain, consistent with a cell-surface-exposed ectodomain.
- No amyloidogenic segments predicted. AstraUNFOLD flags no aggregation-prone stretch — notable given the long intrinsically disordered cytoplasmic tail.
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 |
|---|---|---|
| Surface Pocket in the Ectodomain (AstraBIND, 0.819) | Alanine scan of the flagged ectodomain residues + α-synuclein-fibril binding assay | Reduced fibril binding / uptake — tests the predicted interaction surface |
| Long Disordered Cytoplasmic Tail (337–826) | Truncate to the folded ectodomain for structural work | Improved expression and crystallisability / cryo-EM behaviour |
| Predicted Single-Pass Topology + Surface Glycans (N66 / N201 / N221 / N265) | Surface labelling / glycosidase treatment on intact neurons | Confirms an extracellular, glycosylated ectodomain |
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.
- Barely more than a name. FAM171A2 is IDG Tdark with no catalogued molecular function; its Parkinson's case rests on a single high-profile α-synuclein-uptake study and on genetic association with progranulin and neurodegeneration risk, not on an established mechanism or a validated binding partner. Treat every functional statement here — including the predicted pocket — as a hypothesis.
All predictions were generated with Orbion's Astra suite from the canonical FAM171A2 sequence (UniProt A8MVW0), using AlphaFold-derived structural features. Reported values are model outputs; model internals are out of scope.
References
- [1]UniProt Consortium. UniProtKB entry A8MVW0 (FAM171A2, human). uniprot.org.
- [2]Pharos (Illuminating the Druggable Genome). FAM171A2 target record — Tdark. pharos.nih.gov.
- [3]Wu KM et al. Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson's disease. (2025). https://doi.org/10.1126/science.adp3645
- [4]Xu W et al. The FAM171A2 gene is a key regulator of progranulin expression and modifies the risk of multiple neurodegenerative diseases. (2020). https://doi.org/10.1126/sciadv.abb3063
- [5]Wang Y et al. The role of FAM171A2-GRN-NF-κB pathway in TBBPA induced oxidative stress and inflammatory response in mouse-derived hippocampal neuronal HT22 cells. (2025). https://doi.org/10.1016/j.ecoenv.2024.117445