Novel function of human ADAM15 disintegrin-like domain and its derivatives in platelet aggregation

Ok Hee Jeon, Dongbum Kim, Yong Jun Choi, Seung Hee Kim, Won Seok Choi, Doo Sik Kim

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

Introduction: A Disintegrin and Metalloproteinase (ADAM) proteins are a family of multifunctional proteins containing disintegrin and metalloproteinase domains that perform both adhesive and proteolytic functions in cell-cell and cell-matrix interactions. ADAM15 is unique among these proteins in having an Arg-Gly-Asp (RGD) motif in its disintegrin-like domain. This motif is known to interact with the integrin αIIbβ3 on platelets. Materials and methods: We cloned and expressed the human ADAM15 disintegrin-like domain and its derivatives in Pichia pastoris, and purified them by chromatographic fractionation. We then characterized the integrin binding specificities and their antiplatelet activities of the proteins. Antiplatelet function was assessed by inhibition of platelet adhesion and aggregation. Results: The yeast-expressed ADAM15 disintegrin-like domains were able to inhibit the binding of αIIbβ3 as well as αvβ3 to its biological ligands in a dose-dependent manner. Remarkably, mutation of the three residues proximal to the RGD tripeptide sequence, RPTRGD sequence to NWKRGD, increased its affinity for αIIbβ3. The NWK mutant had a much greater inhibitory action on human platelet aggregation than the original ADAM15 disintegrin-like domain. Conclusions: The structural context of the RGD tripeptide sequence in the disintegrin domain determines the specificity and affinity of the protein for its binding partners. The human ADAM15 disintegrin-like domain may provide useful information for developing an antithrombotic agent.

Original languageEnglish
Pages (from-to)609-619
Number of pages11
JournalThrombosis Research
Volume119
Issue number5
DOIs
Publication statusPublished - 2007

Bibliographical note

Funding Information:
This work was supported by Research Funds from the National Research Laboratory Program (Project No. M1-0400-00-0043) from the Ministry of Science and Technology in Korea.

All Science Journal Classification (ASJC) codes

  • Hematology

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