P885L
Category 3/4 — Most DruggablePathogenic/Likely pathogenicLumenal · predictedσ-1 candidateEditorialProline → Leucine at position 885 inside wolframin's eleventh and final transmembrane helix (TM11). ClinVar Pathogenic/Likely pathogenic with the broadest clinical spectrum documented for any single position in the gene: Wolfram syndrome 1, Wolfram-like syndrome, DFNA6 hearing loss, Cataract 41, type 2 diabetes. AlphaMissense 0.971, DynaMut2 ΔΔG -0.50 kcal/mol (destabilising).
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | N500 | — | Lost |
| Hydrogen bond | — | C505 | Gained |
| Hydrogen bond | — | F883 | Gained |
| Polar contact | — | P504 | Gained |
| Polar contact | — | F883 | Gained |
| Van der Waals | P504 | — | Lost |
| Van der Waals | — | Y508 | Gained |
| Hydrophobic | — | A465 | Gained |
| Hydrophobic | P504 | P504 | Preserved |
| Hydrophobic | — | Y508 | Gained |
Lost / gained / preserved interatomic contacts at the variant residue, from the DynaMut2 (Arpeggio) interaction analysis of the wild-type and energy-minimized mutant structures.
Computational Predictions
Clinical Evidence
Observed at very low frequency in gnomAD.
Structural Context
Position 885 sits inside TM11, the final transmembrane helix of wolframin. The AlphaFold model places P885 within 5 Å of PHE886 (2.5 Å), PHE884 (2.5 Å), PHE883 (4.2 Å), and LEU887 (4.7 Å). The local environment is dominated by aromatic residues — an aromatic cluster (F883, F884, F886) within a single membrane-embedded turn of helix.
The wild-type proline at position 885 is structurally deliberate. Proline residues in transmembrane helices appear in specific positions where the protein needs the helix to kink — they introduce a controlled bend in what would otherwise be a straight α-helix. Proline at position 885, sitting in the middle of three consecutive phenylalanines, almost certainly serves this kinking role: it creates a controlled local geometry that the surrounding aromatic packing depends on.
Replacing proline with leucine removes that controlled kink. Leucine cannot break the helix in the same way — its backbone is free to adopt the standard α-helical phi/psi angles. The result is a TM11 that is more linear than the wild-type, with the aromatic cluster (F883, F884, F886) reorganized accordingly. The interlocking packing that depends on the wild-type kink is lost.
The |ΔΔG| of 0.50 kcal/mol indicates the fold absorbs this rearrangement — TM11 still embeds in the membrane, the protein still folds. But the precise geometry of the C-terminal anchoring region is changed, and the AlphaMissense score of 0.971 reflects severe functional consequence. Notably, C505Y (Atlas card adjacent, in TM6) has PRO885 as a 4.1 Å neighbor — suggesting TM6-TM11 cross-talk in the membrane. Disrupting the P885 kink also affects whatever functional contact TM6 makes through this position.
Druggability Assessment
The mechanism is loss of a deliberate proline-induced helix kink in TM11, perturbing the C-terminal membrane anchoring geometry and disrupting the TM6-TM11 cross-helix contact through C505/P885 (see C505Y Atlas card for the reciprocal view).
The therapeutic strategy is site-directed at the TM11 aromatic cluster: a small molecule that restores the helix geometry the wild-type kink produced, or that occupies the disrupted TM6-TM11 interface, would compensate for the lost kink. The clinical breadth (five distinct phenotypes documented) makes this one of the highest-value docking targets in the WFS1 atlas.
Why this matters
Feed this card to Wolfram Intelligence
Download the P885L PDF below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals — guanidinium mimetics, sigma-1 agonist docking, NAC thiol-capping. NAC is already on the bench-testing list.