8s9e
From Proteopedia
Solution structure of jarastatin (rJast), a disintegrin from Bothrops jararaca
Structural highlights
FunctionVM2JA_BOTJA Binds alpha-5/beta-1 (ITGAV/ITGB1), alpha-V/beta-3 (ITGAV/ITGB3) and alpha-M/beta-2 (ITGAM/ITGB2) integrins. Is a potent inhibitor of platelet aggregation induced by ADP, collagen, and thrombin. Induces neutrophil chemotaxis and inhibits the chemotaxis of human neutrophils toward fMLP, IL-8, and jarastatin itself. Directly activates an integrin-coupled signaling and modulate the MAPK pathway in different ways, leading the neutrophils to express different functional response. Jarastatin-treated neutrophils accumulates F-actin at the plasmalemma. Induces PTK2/FAK1 and phosphoinositide 3-kinase (PI3K) activation. Induces Erk-2 translocation to nucleus and a delay of the spontaneous apoptosis of neutrophils. Increases the IL-8 mRNA levels in neutrophils. When injected simultaneously with melanoma cells in mice, jarastatin, flavoridin (FL) and kistrin (KR), significantly reduce tumor lung colonization. Jarastatin inhibits B16F10 cell growth in vitro. When it interacts with melanoma cells, it induces actin cytoskeleton rearrangement, increasing actin polymerization and PTK2/FAK1 phosphorylation. Interferes with NF-kappaB translocation in melanoma cells.[1] [2] [3] Publication Abstract from PubMedDisintegrins are a family of cysteine-rich small proteins that were first identified in snake venom. The high divergence of disintegrins gave rise to a plethora of functions, all related to the interaction with integrins. Disintegrins evolved to interact selectively with different integrins, eliciting many physiological outcomes and being promising candidates for the therapy of many pathologies. We used NMR to determine the structure and dynamics of the recombinant disintegrin jarastatin (rJast) and its interaction with the cancer-related integrin alphaVbeta3. rJast displayed the canonical fold of a medium-sized disintegrin and showed complex dynamic in multiple timescales. We used NMR experiments to map the interaction of rJast with alphaVbeta3, and molecular docking followed by molecular dynamics (MD) simulation to describe the first structural model of a disintegrin/integrin complex. We showed that not only the RGD loop participates in the interaction, but also the N-terminal domain. rJast plasticity was essential for the interaction with alphaVbeta3 and correlated with the main modes of motion depicted in the MD trajectories. In summary, our study provides novel structural insights that enhance our comprehension of the mechanisms underlying disintegrin functionality. Toward the mechanism of jarastatin (rJast) inhibition of the integrin alphaVbeta3.,Vasconcelos AA, Estrada JC, Caruso IP, Kurtenbach E, Zingali RB, Almeida FCL Int J Biol Macromol. 2024 Jan;255:128078. doi: 10.1016/j.ijbiomac.2023.128078. , Epub 2023 Nov 14. PMID:37972836[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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