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Title | Microfibril-associated glycoprotein 4 forms octamers that mediate interactions with elastogenic proteins and cells. |
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Journal, issue, pages | Nat Commun, Vol. 15, Issue 1, Page 4015, Year 2024 |
Publish date | May 13, 2024 |
Authors | Michael R Wozny / Valentin Nelea / Iram Fatima S Siddiqui / Shaynah Wanga / Vivian de Waard / Mike Strauss / Dieter P Reinhardt / |
PubMed Abstract | Microfibril-associated glycoprotein 4 (MFAP4) is a 36-kDa extracellular matrix glycoprotein with critical roles in organ fibrosis, chronic obstructive pulmonary disease, and cardiovascular ...Microfibril-associated glycoprotein 4 (MFAP4) is a 36-kDa extracellular matrix glycoprotein with critical roles in organ fibrosis, chronic obstructive pulmonary disease, and cardiovascular disorders, including aortic aneurysms. MFAP4 multimerises and interacts with elastogenic proteins, including fibrillin-1 and tropoelastin, and with cells via integrins. Structural details of MFAP4 and its potential interfaces for these interactions are unknown. Here, we present a cryo-electron microscopy structure of human MFAP4. In the presence of calcium, MFAP4 assembles as an octamer, where two sets of homodimers constitute the top and bottom halves of each octamer. Each homodimer is linked together by an intermolecular disulphide bond. A C34S missense mutation prevents disulphide-bond formation between monomers but does not prevent octamer assembly. The atomic model, built into the 3.55 Å cryo-EM map, suggests that salt-bridge interactions mediate homodimer assembly, while non-polar residues form the interface between octamer halves. In the absence of calcium, an MFAP4 octamer dissociates into two tetramers. Binding studies with fibrillin-1, tropoelastin, LTBP4, and small fibulins show that MFAP4 has multiple surfaces for protein-protein interactions, most of which depend upon MFAP4 octamer assembly. The C34S mutation does not affect these protein interactions or cell interactions. MFAP4 assemblies with fibrillin-1 abrogate MFAP4 interactions with cells. |
External links | Nat Commun / PubMed:38740766 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.55 - 7.3 Å |
Structure data | EMDB-42394, PDB-8un7: EMDB-42398: MFAP4 after treatment with EDTA/without Ca2+ |
Chemicals | ChemComp-NAG: ChemComp-CA: |
Source |
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Keywords | CELL ADHESION / MFAP4 Octamer Extracellular Matrix |