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The interaction of integrin ?IIb?3 with fibrin occurs through multiple binding sites in the ?IIb ?-propeller domain.

ABSTRACT: The currently available antithrombotic agents target the interaction of platelet integrin ?IIb?3 (GPIIb-IIIa) with fibrinogen during platelet aggregation. Platelets also bind fibrin formed early during thrombus growth. It was proposed that inhibition of platelet-fibrin interactions may be a necessary and important property of ?IIb?3 antagonists; however, the mechanisms by which ?IIb?3 binds fibrin are uncertain. We have previously identified the ?370-381 sequence (P3) in the ?C domain of fibrinogen as the fibrin-specific binding site for ?IIb?3 involved in platelet adhesion and platelet-mediated fibrin clot retraction. In the present study, we have demonstrated that P3 can bind to several discontinuous segments within the ?IIb ?-propeller domain of ?IIb?3 enriched with negatively charged and aromatic residues. By screening peptide libraries spanning the sequence of the ?IIb ?-propeller, several sequences were identified as candidate contact sites for P3. Synthetic peptides duplicating these segments inhibited platelet adhesion and clot retraction but not platelet aggregation, supporting the role of these regions in fibrin recognition. Mutant ?IIb?3 receptors in which residues identified as critical for P3 binding were substituted for homologous residues in the I-less integrin ?M?2 exhibited reduced cell adhesion and clot retraction. These residues are different from those that are involved in the coordination of the fibrinogen ?404-411 sequence and from auxiliary sites implicated in binding of soluble fibrinogen. These results map the binding of fibrin to multiple sites in the ?IIb ?-propeller and further indicate that recognition specificity of ?IIb?3 for fibrin differs from that for soluble fibrinogen.

SUBMITTER: Podolnikova NP

PROVIDER: S-EPMC3900980 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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The interaction of integrin αIIbβ3 with fibrin occurs through multiple binding sites in the αIIb β-propeller domain.

Podolnikova Nataly P NP Yakovlev Sergiy S Yakubenko Valentin P VP Wang Xu X Gorkun Oleg V OV Ugarova Tatiana P TP

The Journal of biological chemistry 20131212 4

The currently available antithrombotic agents target the interaction of platelet integrin αIIbβ3 (GPIIb-IIIa) with fibrinogen during platelet aggregation. Platelets also bind fibrin formed early during thrombus growth. It was proposed that inhibition of platelet-fibrin interactions may be a necessary and important property of αIIbβ3 antagonists; however, the mechanisms by which αIIbβ3 binds fibrin are uncertain. We have previously identified the γ370-381 sequence (P3) in the γC domain of fibrino ...[more]

PMID: 24338009

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Project description:Integrins are heterodimeric cell-surface receptors with key functions in cell-cell and cell-matrix adhesion. Integrin α and β subunits are present throughout the metazoans, but it is unclear whether the subunits predate the origin of multicellular organisms. Several component domains have been detected in bacteria, one of which, a specific 7-bladed β-propeller domain, is a unique feature of the integrin α subunits. Here, we describe a structure-derived motif, which incorporates key features of each blade from the X-ray structures of human αIIbβ3 and αVβ3, includes elements of the FG-GAP/Cage and Ca(2+)-binding motifs, and is specific only for the metazoan integrin domains. Separately, we searched for the metazoan integrin type β-propeller domains among all available sequences from bacteria and unicellular eukaryotic organisms, which must incorporate seven repeats, corresponding to the seven blades of the β-propeller domain, and so that the newly found structure-derived motif would exist in every repeat. As the result, among 47 available genomes of unicellular eukaryotes we could not find a single instance of seven repeats with the motif. Several sequences contained three repeats, a predicted transmembrane segment, and a short cytoplasmic motif associated with some integrins, but otherwise differ from the metazoan integrin α subunits. Among the available bacterial sequences, we found five examples containing seven sequential metazoan integrin-specific motifs within the seven repeats. The motifs differ in having one Ca(2+)-binding site per repeat, whereas metazoan integrins have three or four sites. The bacterial sequences are more conserved in terms of motif conservation and loop length, suggesting that the structure is more regular and compact than those example structures from human integrins. Although the bacterial examples are not full-length integrins, the full-length metazoan-type 7-bladed β-propeller domains are present, and sometimes two tandem copies are found.

Dataset Information

The interaction of integrin ?IIb?3 with fibrin occurs through multiple binding sites in the ?IIb ?-propeller domain.

Publications

The interaction of integrin αIIbβ3 with fibrin occurs through multiple binding sites in the αIIb β-propeller domain.

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