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Microfibril-associated glycoprotein 4 forms octamers that mediate interactions with elastogenic proteins and cells
Open accessPreprint — published as 10.1038/s41467-024-48377-z · Paper page
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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Highly accurate protein structure prediction with AlphaFold
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Metadata
- Authors
- Wozny, M. R., Nelea, V., Siddiqui, I. F. S., Wanga, S., de Waard, V., Strauss, M., & Reinhardt, D. P.
- Affiliations
- McGill University (CA)
- Amsterdam UMC Location University of Amsterdam (NL)
- Corresponding author
- Strauss, Mike
- Reinhardt, Dieter P.
- ORCID
- Venue
- Nature Communications
- Publisher
- openRxiv
- Published
- 2023-09-22
- Volume
- 15
- Issue
- 1
- Pages
- 4015-4015
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC11091212
- OpenAlex
- W4396871334
- Cited by
- 9
- References
- 1
- Citations by year
- 2026: 3 · 2025: 6
- FWCI
- 2.38
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship@McGill (McGill) (submittedVersion, cc-by)
- Pure Amsterdam UMC (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Government of Canada (RGPIN-2022-05045, MFE-187851, PJT-186194, RGPIN-2020-04837)
- Canadian Institutes of Health Research (187851_1, 186194_1)
- Natural Sciences and Engineering Research Council of Canada (RGPIN 2020, rgpin-2022-05045, -2022, 04837, rgpin-2020-04837)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Keywords
- MFAP4, homodimer, disulfide bonds, salt bridges, protein-protein interaction, fibrillin-1, tropoelastin, LTBP4, fibulin, integrin binding, extracellular matrix glycoprotein, organ fibrosis, aortic aneurysm, chronic obstructive pulmonary disease
- MeSH terms
- Fibrillin-1, Calcium, Carrier Proteins, Glycoproteins, Humans, Models, Molecular, Protein Binding, Tropoelastin, Extracellular Matrix Proteins, Mutation, Missense, Cryoelectron Microscopy, Microfibrils, Adipokines, Protein Multimerization, HEK293 Cells
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