| Autor: |
Kanagasabai, Vadivel, Yogesh, Kumar, Matthew W, Bunce, Rodney M, Camire, Madhu S, Bajaj, S Paul, Bajaj |
| Rok vydání: |
2017 |
| Předmět: |
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| Zdroj: |
International biology review. 1(1) |
| Popis: |
Factor V (FV) B-domain contains an acidic region (FV-AR2) and a basic region (FV-BR), which interact with each other and maintain FV in a procofactor form; removal of either region via deletion/proteolysis results in an active FVa molecule. Tissue factor pathway inhibitor type-1 (TFPI) and type-2 (TFPI2) each contain a C-terminus basic segment homologous to FV-BR; this region in TFPI (and predicted in TFPI2) binds to FV-AR2 in platelet FVa (that lacks FV-BR) with high affinity and inhibits FVa function.To understand molecular interactions between FV-AR2 with FV-BR, TFPI-BR and TFPI2-BR.Circular dichroism (CD) and molecular modeling approaches.CD experiments reveal the presence of ∼20% helical content in both FV-AR2 and FV-BR but each lacks beta-sheet. Predicted structures of FV-AR2 and FV-BR, obtained using threading (I-TASSER), are consistent with the CD data and have compact folds with hydrophobic residues in the interior and charged residues on the surface. Scores from QMEAN and ModFOLD servers indicate a very high probability for each structure to be native. Predicted models of Kunitz domain-3 of TFPI and TFPI2 each with C-terminal basic tail are consistent with known homologous structures. Docking experiments using ClusPro indicate that the acidic groove of FV-AR2 has high shape complementarity to accommodate the conserved basic residues in FV-BR (1002-RKKKK-1006), TFPI-BR (256-RKRKK-260) or TFPI2-BR (191-KKKKK-195). Further, similar electrostatic interactions occur in each case. These models, in the absence of experimentally determined structures, provide a guiding point for proper mutagenesis studies in FV, TFPI and TFPI2. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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