@article{HanRenMamtiminetal.2023,
  author    = {Han, Chao and Ren, Pengxuan and Mamtimin, Medina and Kruk, Linus and Sarukhanyan, Edita and Li, Chenyu and Anders, Hans-Joachim and Dandekar, Thomas and Krueger, Irena and Elvers, Margitta and Goebel, Silvia and Adler, Kristin and M{\"u}nch, G{\"o}tz and Gudermann, Thomas and Braun, Attila and Mammadova-Bach, Elmina},
  title     = {Minimal collagen-binding epitope of glycoprotein VI in human and mouse platelets},
  series = {Biomedicines},
  volume    = {11},
  journal   = {Biomedicines},
  number    = {2},
  issn      = {2227-9059},
  doi       = {10.3390/biomedicines11020423},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304148},
  year      = {2023},
  abstract  = {Glycoprotein VI (GPVI) is a platelet-specific receptor for collagen and fibrin, regulating important platelet functions such as platelet adhesion and thrombus growth. Although the blockade of GPVI function is widely recognized as a potent anti-thrombotic approach, there are limited studies focused on site-specific targeting of GPVI. Using computational modeling and bioinformatics, we analyzed collagen- and CRP-binding surfaces of GPVI monomers and dimers, and compared the interacting surfaces with other mammalian GPVI isoforms. We could predict a minimal collagen-binding epitope of GPVI dimer and designed an EA-20 antibody that recognizes a linear epitope of this surface. Using platelets and whole blood samples donated from wild-type and humanized GPVI transgenic mice and also humans, our experimental results show that the EA-20 antibody inhibits platelet adhesion and aggregation in response to collagen and CRP, but not to fibrin. The EA-20 antibody also prevents thrombus formation in whole blood, on the collagen-coated surface, in arterial flow conditions. We also show that EA-20 does not influence GPVI clustering or receptor shedding. Therefore, we propose that blockade of this minimal collagen-binding epitope of GPVI with the EA-20 antibody could represent a new anti-thrombotic approach by inhibiting specific interactions between GPVI and the collagen matrix.},
  language  = {en}
}
@article{KooMatthewsHarrisonetal.2022,
  author    = {Koo, Chek Ziu and Matthews, Alexandra L. and Harrison, Neale and Szyroka, Justyna and Nieswandt, Bernhard and Gardiner, Elizabeth E. and Poulter, Natalie S. and Tomlinson, Michael G.},
  title     = {The platelet collagen receptor GPVI is cleaved by Tspan15/ADAM10 and Tspan33/ADAM10 molecular scissors},
  series = {International Journal of Molecular Sciences},
  volume    = {23},
  journal   = {International Journal of Molecular Sciences},
  number    = {5},
  issn      = {1422-0067},
  doi       = {10.3390/ijms23052440},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284468},
  year      = {2022},
  abstract  = {The platelet-activating collagen receptor GPVI represents the focus of clinical trials as an antiplatelet target for arterial thrombosis, and soluble GPVI is a plasma biomarker for several human diseases. A disintegrin and metalloproteinase 10 (ADAM10) acts as a 'molecular scissor' that cleaves the extracellular region from GPVI and many other substrates. ADAM10 interacts with six regulatory tetraspanin membrane proteins, Tspan5, Tspan10, Tspan14, Tspan15, Tspan17 and Tspan33, which are collectively termed the TspanC8s. These are emerging as regulators of ADAM10 substrate specificity. Human platelets express Tspan14, Tspan15 and Tspan33, but which of these regulates GPVI cleavage remains unknown. To address this, CRISPR/Cas9 knockout human cell lines were generated to show that Tspan15 and Tspan33 enact compensatory roles in GPVI cleavage, with Tspan15 bearing the more important role. To investigate this mechanism, a series of Tspan15 and GPVI mutant expression constructs were designed. The Tspan15 extracellular region was found to be critical in promoting GPVI cleavage, and appeared to achieve this by enabling ADAM10 to access the cleavage site at a particular distance above the membrane. These findings bear implications for the regulation of cleavage of other ADAM10 substrates, and provide new insights into post-translational regulation of the clinically relevant GPVI protein.},
  language  = {en}
}