- Fold
- Eight predicted transmembrane helices; a multi-pass anoctamin / TMEM16-family membrane protein.
- Pore-Lining Surface
- AstraBIND pore / interface hypothesis (confidence 0.654, medium) around TM6 — a residue-level starting point for mutagenesis; no validated ligand.
- Structural Anchors
- N-glycosylation at six predicted sites, including N335 (UniProt).
- Flexible Regions
- Elevated predicted disorder at the N-terminus (1–64) and C-tail (883–910) — the cytoplasmic termini and natural truncation boundaries.
- Clean Signal
- Aggregation-prone segment flagged (max 0.528).
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 membrane-protein families have been structurally explored. ANO5 has not: an IDG Tbio anoctamin with no experimental structure in the PDB and only a handful of functional studies. UniProt notes a role in annexin-dependent plasma-membrane repair and, pointedly, that it does not show the calcium-activated chloride-channel activity of some family members — so even its molecular function is unsettled. What is firm is the disease link: recessive loss-of-function ANO5 variants underlie limb-girdle muscular dystrophy (LGMD2L / LGMDR12) and Miyoshi myopathy, while a dominant gain-of-function variant causes gnathodiaphyseal dysplasia.
That combination — a solid disease association with near-zero structural information — is where prediction earns its keep: everything below is computed from the canonical 913-residue sequence, with no experimental ANO5 structure used as input.
Architecture & Topology
How the Sequence Is Organised
| Element | Residues | Note |
|---|---|---|
| Transmembrane Helices | 8 predicted | Boundaries: 300–320; 381–401; 463–483; 512–532; 558–578; 680–700; 733–753; 835–855. |
The Predicted Pocket
The Predicted Pore-Lining Surface
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 pore / gating interface
Post-Translational & Structural Features
Specific, Testable Residues
- N-glycosylation at six predicted sites (N335, N366, N380, N768, N778, N791) — extracellular-loop modifications (UniProt).
- Aggregation-prone segment flagged (AstraUNFOLD amyloid max 0.528) — worth screening in 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 |
|---|---|---|
| Predicted Pore / Interface Residues (TM6) | Alanine scan at the predicted TM6 residues + membrane-repair / scrambling assay | Functional change — tests the predicted site |
| Disordered Termini (1–64; 883–910) | N- and C-terminal truncation | Improved expression / thermostability for cryo-EM |
| Predicted Anoctamin / Scramblase Function | Lipid-scrambling / membrane-repair assay | Confirm the predicted functional class |
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.
- Thin biology. ANO5's molecular function is unsettled — it is reported in plasma-membrane repair and lipid scrambling rather than as a chloride channel — and the disease rationale rests chiefly on LGMD2L and gnathodiaphyseal-dysplasia genetics. Treat mechanism as a hypothesis.
All predictions were generated with Orbion's Astra suite from the canonical ANO5 sequence (UniProt Q75V66), using AlphaFold-derived structural features. Reported values are model outputs; model internals are out of scope.
References
- [1]UniProt Consortium. UniProtKB entry Q75V66 (ANO5, human). uniprot.org.
- [2]Pharos (Illuminating the Druggable Genome). ANO5 target record — Tbio. pharos.nih.gov.
- [3]Penttilä S et al. Eight new mutations and the expanding phenotype variability in muscular dystrophy caused by ANO5. (2012). https://doi.org/10.1212/wnl.0b013e31824c4682
- [4]Savarese M et al. Next generation sequencing on patients with LGMD and nonspecific myopathies: Findings associated with ANO5 mutations. (2015). https://doi.org/10.1016/j.nmd.2015.03.011
- [5]Di Zanni E et al. Gain of function of TMEM16E/ANO5 scrambling activity caused by a mutation associated with gnathodiaphyseal dysplasia. (2018). https://doi.org/10.1007/s00018-017-2704-9