Modulation of the Oligomerization of Myelin Proteolipid Protein by Transmembrane Helix Interaction Motifs
Bibliographic record
Abstract
Proteolipid protein (PLP) is a highly hydrophobic 276-residue integral membrane protein that constitutes more than 50% of the total protein in central nervous system myelin. Previous studies have shown that this protein exists in myelin as an oligomer rather than as a monomer, and mutations in PLP that lead to neurological disorders such as Pelizaeus-Merzbacher disease and spastic paraplegia type 2 have been reported to affect its normal oligomerization. Here we employ peptide-based and in vivo approaches to examine the role of the TM domain in the formation of PLP quaternary structure through homo-oligomeric helix-helix interactions. Focusing on the TM4 alpha-helix (sequence (239)FIAAFVGAAATLVSLLTFMIAATY(262)), the site of several disease-causing point mutations that involve putative small residue helix-helix interaction motifs in the TM4 sequence, we used SDS-PAGE, fluorescence resonance energy transfer, size-exclusion chromatography, and TOXCAT assays in an Escherichia coli membrane to show that the PLP TM4 helix readily assembles into varying oligomeric states. In addition, through targeted studies of the PLP TM4 alpha-helix with point mutations that selectively eliminate these small residue motifs via substitution of Gly, Ala, or Ser residues with Ile residues, we describe a potential mechanism through which disease-causing point mutations can lead to aberrant PLP assembly. The overall results suggest that TM segments in misfolded PLP monomers that expose and/or create surface-exposed helix-helix interaction sites that are normally masked may have consequences for disease.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".