- Fold
- Multi-pass endoplasmic-reticulum membrane protein; six transmembrane helices predicted (boundaries in the domain map).
- Binding Pocket
- A residue-level membrane-facing pocket from AstraBIND (confidence 0.897) — a starting point for docking or mutagenesis, not a validated ligand.
- Structural Anchors
- N-linked glycosylation at N91, N101 and N229 (UniProt), on the large loop between TM1 and TM2.
- Flexible Regions
- A short disordered loop (146–156) is the main flexible insert — a natural boundary for construct or truncation design.
- Clean Signal
- Not entirely clean: one aggregation-prone segment flagged (AstraUNFOLD amyloid max 0.545) — screen it out 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 protein families have been structurally explored; CLPTM1L has not. It is an IDG Tbio multi-pass membrane protein with no experimental structure in the PDB and a functional literature only recently taking shape. UniProt describes it as a lipid scramblase that flips glucosaminyl-phosphatidylinositol (GlcN-PI) across the endoplasmic-reticulum membrane during GPI-anchor biosynthesis, and can move other phospholipids in vitro. Its prominence, though, is genetic: CLPTM1L lies at the TERT-CLPTM1L locus on chromosome 5p15.33, whose common variants have been tied to lung and many other cancer types.
That combination — a much-associated cancer-risk locus, near-zero structural information — is where prediction earns its keep: everything below is computed from the canonical 538-residue sequence with Orbion's Astra suite, with no experimental CLPTM1L 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 | 6 predicted | Boundaries: 11–31; 285–305; 325–342; 347–364; 403–423; 429–449. |
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 membrane-facing cavity
Post-Translational & Structural Features
Specific, Testable Residues
- N-glycosylation at position 91, 101, 229 (UniProt) — three N-linked sequons on the large loop between TM1 and TM2, a handle for validating membrane topology.
- Aggregation-prone segment flagged (AstraUNFOLD amyloid max 0.545) — a single hydrophobic stretch worth screening out or mutating before recombinant expression.
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 |
|---|---|---|
| Membrane-Facing Pocket (AstraBIND, 0.897) | Docking + alanine scan of the TM2 / TM4 / TM6 pocket residues | Binding or lipid-transport change at the predicted cavity |
| Predicted Scramblase / Lipid-Transport Function | Reconstituted phospholipid-scramblase assay (GlcN-PI / PI flip) | Confirms the lipid-translocation annotation |
| Disordered Loop (146–156) | Loop deletion or fusion-partner insertion | Improved expression / thermostability for structural work |
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.
- Association, not mechanism. CLPTM1L's cancer link is genetic — it shares the 5p15.33 locus with TERT, so many of the risk signals there could reflect its neighbour rather than CLPTM1L itself — and its scramblase role, though demonstrated in vitro, is not obviously the cancer-relevant one. Treat the target rationale as a hypothesis.
All predictions were generated with Orbion's Astra suite from the canonical CLPTM1L sequence (UniProt Q96KA5), using AlphaFold-derived structural features. Reported values are model outputs; model internals are out of scope.
References
- [1]UniProt Consortium. UniProtKB entry Q96KA5 (CLPTM1L, human). uniprot.org.
- [2]Pharos (Illuminating the Druggable Genome). CLPTM1L target record — Tbio. pharos.nih.gov.
- [3]Wang Y, Menon AK, Maki Y, et al. Genome-wide CRISPR screen reveals CLPTM1L as a lipid scramblase required for efficient GPI biosynthesis. Proc. Natl. Acad. Sci. USA (2022). https://doi.org/10.1073/pnas.2115083119
- [4]Rafnar T et al. Sequence variants at the TERT-CLPTM1L locus associate with many cancer types. (2009). https://doi.org/10.1038/ng.296
- [5]Haiman CA et al. A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer. (2011). https://doi.org/10.1038/ng.985
- [6]Lan Q et al. Longer telomere length in peripheral white blood cells is associated with risk of lung cancer and the rs2736100 (CLPTM1L-TERT) polymorphism in a prospective cohort study among women in China. (2013). https://doi.org/10.1371/journal.pone.0059230