Microfibril-associated glycoprotein 4 forms octamers that mediate interactions with elastogenic proteins and cells.
Humans
Fibrillin-1
/ metabolism
Tropoelastin
/ metabolism
Cryoelectron Microscopy
Extracellular Matrix Proteins
/ metabolism
Protein Multimerization
Protein Binding
Models, Molecular
Calcium
/ metabolism
Mutation, Missense
Microfibrils
/ metabolism
HEK293 Cells
Carrier Proteins
Glycoproteins
Adipokines
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
13 May 2024
13 May 2024
Historique:
received:
28
09
2023
accepted:
29
04
2024
medline:
14
5
2024
pubmed:
14
5
2024
entrez:
13
5
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 38740766
doi: 10.1038/s41467-024-48377-z
pii: 10.1038/s41467-024-48377-z
doi:
Substances chimiques
Fibrillin-1
0
Tropoelastin
0
MFAP4 protein, human
0
Extracellular Matrix Proteins
0
FBN1 protein, human
0
Calcium
SY7Q814VUP
Carrier Proteins
0
Glycoproteins
0
Adipokines
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
4015Subventions
Organisme : Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (Conseil de Recherches en Sciences Naturelles et en Génie du Canada)
ID : RGPIN-2022-05045
Organisme : Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (Conseil de Recherches en Sciences Naturelles et en Génie du Canada)
ID : RGPIN-2020-04837
Organisme : Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)
ID : MFE-187851
Organisme : Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)
ID : PJT-186194
Informations de copyright
© 2024. The Author(s).
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