The α4β1/EMILIN1 interaction discloses a novel and unique integrin-ligand type of engagement

Alessandra Capuano, Federico Fogolari, Francesco Bucciotti, Paola Spessotto, Pier Andrea Nicolosi, Maria Teresa Mucignat, Marta Cervi, Gennaro Esposito, Alfonso Colombatti, Roberto Doliana

Research output: Contribution to journalArticle

Abstract

EMILIN1, a homo-trimeric adhesive ECM glycoprotein, interacts with the α4β1 integrin through its gC1q domain. Uniquely among the C1q family members, the EMILIN1 gC1q presents only nine-stranded β-sandwich fold and the missing strand is substituted by a disordered 19-residue long segment spanning from Y927 to G945 at the apex of the gC1q domain. This unstructured loop exposes to the solvent the acidic residue E933, which plays a key role in the α4β1 integrin mediated interaction. Here, we experimentally determined that the three E933 residues (one from each monomer) are all required for ligand binding. By docking the NMR structure of the gC1q to a virtual α4β1 crystal structure based on the known structures of α4β7 and α5β1 integrins we built a model of α4β1-gC1q complex where three E933 residues are smoothly forced to coordinate the Mg2 + ion at the βI MIDAS site of the integrin. By bringing the three E933 close in space, the trimeric supramolecular organization of gC1q allows the formation of a proper 3D geometry and suggests a quaternary-structure-dependent mode of interaction. Furthermore, we experimentally identified R904 as a synergistic residue for cell adhesion. Accordingly, the model showed that this residue is able to form potential stabilizing intra-chain salt bridges with residues E928 and E930. This mode of interaction likely accounts for a more stable and durable α4β1-gC1q interaction in comparison with the prototypic CS1 ligand. To our knowledge, this is the first report describing the simultaneous involvement of all the three acidic residues of a trimeric ligand in the formation of a dimeric complex with the integrin βI domain.

Original languageEnglish
Pages (from-to)50-66
Number of pages17
JournalMatrix Biology
Volume66
DOIs
Publication statusPublished - Mar 1 2018

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Integrins
Ligands
Cell Adhesion
Adhesives
Glycoproteins
Salts
Ions

Keywords

  • Adhesion
  • EMILIN1
  • Extracellular matrix
  • gC1q
  • Homo-trimer
  • α4β1 integrin

ASJC Scopus subject areas

  • Molecular Biology

Cite this

The α4β1/EMILIN1 interaction discloses a novel and unique integrin-ligand type of engagement. / Capuano, Alessandra; Fogolari, Federico; Bucciotti, Francesco; Spessotto, Paola; Nicolosi, Pier Andrea; Mucignat, Maria Teresa; Cervi, Marta; Esposito, Gennaro; Colombatti, Alfonso; Doliana, Roberto.

In: Matrix Biology, Vol. 66, 01.03.2018, p. 50-66.

Research output: Contribution to journalArticle

Capuano, Alessandra ; Fogolari, Federico ; Bucciotti, Francesco ; Spessotto, Paola ; Nicolosi, Pier Andrea ; Mucignat, Maria Teresa ; Cervi, Marta ; Esposito, Gennaro ; Colombatti, Alfonso ; Doliana, Roberto. / The α4β1/EMILIN1 interaction discloses a novel and unique integrin-ligand type of engagement. In: Matrix Biology. 2018 ; Vol. 66. pp. 50-66.
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AU - Bucciotti, Francesco

AU - Spessotto, Paola

AU - Nicolosi, Pier Andrea

AU - Mucignat, Maria Teresa

AU - Cervi, Marta

AU - Esposito, Gennaro

AU - Colombatti, Alfonso

AU - Doliana, Roberto

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AB - EMILIN1, a homo-trimeric adhesive ECM glycoprotein, interacts with the α4β1 integrin through its gC1q domain. Uniquely among the C1q family members, the EMILIN1 gC1q presents only nine-stranded β-sandwich fold and the missing strand is substituted by a disordered 19-residue long segment spanning from Y927 to G945 at the apex of the gC1q domain. This unstructured loop exposes to the solvent the acidic residue E933, which plays a key role in the α4β1 integrin mediated interaction. Here, we experimentally determined that the three E933 residues (one from each monomer) are all required for ligand binding. By docking the NMR structure of the gC1q to a virtual α4β1 crystal structure based on the known structures of α4β7 and α5β1 integrins we built a model of α4β1-gC1q complex where three E933 residues are smoothly forced to coordinate the Mg2 + ion at the βI MIDAS site of the integrin. By bringing the three E933 close in space, the trimeric supramolecular organization of gC1q allows the formation of a proper 3D geometry and suggests a quaternary-structure-dependent mode of interaction. Furthermore, we experimentally identified R904 as a synergistic residue for cell adhesion. Accordingly, the model showed that this residue is able to form potential stabilizing intra-chain salt bridges with residues E928 and E930. This mode of interaction likely accounts for a more stable and durable α4β1-gC1q interaction in comparison with the prototypic CS1 ligand. To our knowledge, this is the first report describing the simultaneous involvement of all the three acidic residues of a trimeric ligand in the formation of a dimeric complex with the integrin βI domain.

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