SH2-mediated steric occlusion of the C2 domain regulates autoinhibition of SHIP1 inositol 5-phosphatase
Bibliographic record
Abstract
The Src homology 2 (SH2) domain-containing inositol polyphosphate 5-phosphatase 1 (SHIP1) is an immune cell-specific enzyme that regulates phosphatidylinositol-(3,4,5)-trisphosphate signaling at the plasma membrane following receptor activation. SHIP1 plays an important role in processes, such as directed cell migration, endocytosis, and cortical membrane oscillations. Alterations in SHIP1 expression have been shown to perturb myeloid cell chemotaxis and differentiation. In the brain, SHIP1 regulates microglial cell behaviors, which have been linked to Alzheimer's disease. Understanding the structural and functional relationships of SHIP1 is critical for developing ways to modulate SHIP1 membrane localization and lipid phosphatase activity during immune cell signaling. Recently, we discovered that the N-terminal SH2 domain of SHIP1 suppresses lipid phosphatase activity. SHIP1 autoinhibition can be relieved through interactions with receptor-derived phosphotyrosine peptides presented on membranes or in solution. Using hydrogen-deuterium exchange mass spectrometry, we identified intramolecular contacts between the N-terminal SH2 domain and the CBL1 motif of the C2 domain that limit SHIP1 membrane localization and activity. Single-molecule measurements of purified SHIP1 on supported lipid bilayers and in neutrophil-like cells support a model in which the SH2 domain blocks membrane binding of the central catalytic module. Mutations that disrupt autoinhibition enhance the membrane binding frequency and increase the catalytic efficiency of SHIP1. Although dimerization of SHIP1 enhances membrane localization and the apparent phosphatase activity, it is not required for SHIP1 autoinhibition. Overall, our results provide new insight concerning SHIP1's structural organization, membrane binding dynamics, and the mechanism of autoinhibition.
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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".