- Fold
- Predicted soluble, multi-domain protein — an N-terminal kinase-like (pseudokinase) domain (14–314) followed by an extended, partly disordered C-terminal region.
- Allosteric Pocket
- AstraBIND allosteric-candidate hypothesis (confidence 0.65) — a residue-level starting point for docking / mutagenesis; no validated ligand, and no catalytic activity expected.
- Flexible Regions
- Elevated predicted disorder across a C-terminal loop (553–585) — a natural construct / truncation boundary.
- Clean Signal
- One aggregation-prone segment flagged (AstraUNFOLD amyloid max 0.512) — worth screening in 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 enzyme families have been structurally explored. SCYL1 has not: an IDG Tbio target with no experimental structure in the PDB and only a handful of functional studies. It is a SCY1-like pseudokinase — its N-terminal domain adopts a kinase fold but is predicted to be catalytically inactive — that works in COPI-mediated retrograde trafficking between the Golgi and the ER. Its clinical importance is not in doubt: recessive loss-of-function mutations cause CALFAN — an inherited syndrome of low-γ-GT cholestasis, acute liver failure and spinocerebellar neurodegeneration. Yet for the protein itself there is almost nothing structural to look up.
That combination — a clear disease link, near-zero structural information — is where prediction earns its keep: everything below is computed from the canonical 808-residue sequence with Orbion's Astra suite, with no experimental SCYL1 structure used as input. Because SCYL1 is a pseudokinase, we treat the model's kinase-fold signal as a scaffold, and its predicted pocket as an allosteric / regulatory site rather than a catalytic active site.
Architecture & Topology
How the Sequence Is Organised
| Element | Residues | Note |
|---|---|---|
| Protein Kinase | 14–314 | UniProt-annotated domain. |
The Predicted Pocket
A Predicted Allosteric Pocket
A residue-level allosteric-candidate hypothesis from AstraBIND. SCYL1 is a pseudokinase with no catalytic activity, and AstraBIND has no ligand-bound relative to retrieve from — so this is a low-confidence, structure-based surface. The residues sit within the pseudokinase domain and are offered as a regulatory / interaction-surface hypothesis, not a druggable pocket or an enzyme-inhibition site.
Site: Predicted substrate / cofactor-facing residues
Post-Translational & Structural Features
Specific, Testable Residues
- Protein kinase domain (14–314) — the UniProt-annotated N-terminal kinase-like fold; in SCYL1 this is a pseudokinase, predicted to act as a scaffolding / interaction module rather than a catalytically active enzyme.
- Aggregation-prone segment flagged (AstraUNFOLD amyloid max 0.512) — a short hydrophobic stretch worth screening or engineering out when designing a soluble construct.
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 |
|---|---|---|
| Allosteric Pocket Residues (93–96) | Alanine scan at the predicted pocket + binding / co-immunoprecipitation with COPI partners | Change in partner binding or Golgi-trafficking function (binding, not catalysis) |
| Disordered / Flexible Regions | Fusion-partner insertion or terminal truncation | Improved expression / thermostability for structural work |
| Predicted Soluble, Cytoplasmic Localisation | Fractionation / imaging for Golgi–ER association | Confirm soluble, COPI-linked trafficking role |
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.
- A pseudokinase, not an active enzyme. SCYL1's kinase-like domain is predicted to be catalytically dead, so the model's kinase-activity signal reflects fold, not function — there is no catalytic reaction to assay. Its established role is scaffolding COPI-mediated Golgi–ER traffic, and its disease link (recessive loss-of-function causing CALFAN — low-γ-GT cholestasis, acute liver failure and spinocerebellar neurodegeneration) is genetic; the older transcriptional-activator annotation is weakly supported. Treat the mechanism, and any pocket, as a binding / regulatory hypothesis rather than an enzyme-inhibition target.
All predictions were generated with Orbion's Astra suite from the canonical SCYL1 sequence (UniProt Q96KG9), using AlphaFold-derived structural features. Reported values are model outputs; model internals are out of scope.
References
- [1]UniProt Consortium. UniProtKB entry Q96KG9 (SCYL1, human). uniprot.org.
- [2]Pharos (Illuminating the Druggable Genome). SCYL1 target record — Tbio. pharos.nih.gov.
- [3]Burman JL et al. Scyl1, mutated in a recessive form of spinocerebellar neurodegeneration, regulates COPI-mediated retrograde traffic. (2008). https://doi.org/10.1074/jbc.m801869200
- [4]Schmidt WM et al. Mutation in the Scyl1 gene encoding amino-terminal kinase-like protein causes a recessive form of spinocerebellar neurodegeneration. (2007). https://doi.org/10.1038/sj.embor.7401001
- [5]Burman JL et al. Scyl1 regulates Golgi morphology. (2010). https://doi.org/10.1371/journal.pone.0009537