Microfibril-associated glycoprotein 4 forms octamers that mediate interactions with elastogenic proteins and cells
Bibliographic record
Abstract
Abstract Microfibrillar-associated protein 4 (MFAP4) is a 36-kDa extracellular glycoprotein with critical roles in human pathologies, including fibrosis in several organ systems, chronic obstructive pulmonary disease, and cardiovascular disorders. In elastic tissues such as arteries, lungs, and skin, MFAP4 associates with microfibrils and elastic fibres, which are the central extracellular fibres affected in thoracic aneurysms. MFAP4 directly interacts with elastogenic proteins, including fibrillin-1 and tropoelastin, and with cells via integrins. MFAP4 multimerisation represents a critical hallmark required for its physiological and pathological properties. However, molecular details and functional consequences of MFAP4 multimerisation are lacking. Here we present a cryo-electron microscopy structure of human MFAP4. In the presence of calcium, MFAP4 assembles as an octamer with D2 point group symmetry, where two sets of homodimers constitute the top and bottom halves of each octamer. Each of the homodimers is linked together by an inter-molecular disulfide bond. An engineered C34S missense mutation in MFAP4 prevented disulfide-bond formation between monomers, but the mutant formed octamers similar to wild type MFAP4. The atomic model, built into the 3.55 Å cryo-EM map, suggests that several salt-bridges are important for interactions within and between homodimers, while non-polar interactions are important for octamer halves to assemble. In the absence of calcium, MFAP4 dissociates into tetramers, representing the top/bottom halves of the octamers. Binding studies with elastogenic proteins, including fibrillin-1, tropoelastin, LTBP4, and small fibulins showed that MFAP4 has multiple surfaces for protein-protein interactions, which depend upon the higher-order assembly of MFAP4. While the disulfide-bond mediated by C34S contributes little to those protein interactions, it modulated cell interaction. When MFAP4 forms assemblies with fibrillin-1, it abrogates MFAP4 interactions with cells. Overall, the study provides detailed molecular structure-function relationships of MFAP4 interactions with elastogenic proteins and cells.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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) | 0.001 | 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 source (direct Gemma or distilled Codex), 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".