8UN7

Single particle analysis of recombinant human MFAP4

Summary for 8UN7

• Entry DOI: 10.2210/pdb8un7/pdb
• EMDB information: 42394
• Descriptor: Microfibril-associated glycoprotein 4, 2-acetamido-2-deoxy-beta-D-glucopyranose, CALCIUM ION (3 entities in total)
• Functional Keywords: mfap4 octamer extracellular matrix, cell adhesion
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 8
• Total formula weight: 239385.11

Authors

Wozny, M.W.,Nelea, V. (deposition date: 2023-10-18, release date: 2024-05-22, Last modification date: 2024-10-23)

Primary citation

Wozny, M.R.,Nelea, V.,Siddiqui, I.F.S.,Wanga, S.,de Waard, V.,Strauss, M.,Reinhardt, D.P.
Microfibril-associated glycoprotein 4 forms octamers that mediate interactions with elastogenic proteins and cells.
Nat Commun, 15:4015-4015, 2024

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 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.

PubMed: 38740766
DOI: 10.1038/s41467-024-48377-z

Experimental method

ELECTRON MICROSCOPY (3.55 Å)