Long-Ranged Protein-Glycan Interactions Stabilize Von Willebrand Factor A2 Domain from Mechanical Unfolding
| Autor: | Whitney Lai, Jumin Lee, Chuqiao Dong, X. Frank Zhang, Alparslan Oztekin, Seonghoon Kim, Edmund B. Webb, Wonpil Im |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Glycan Multiprotein complex Protein Conformation Biophysics lcsh:Medicine ADAMTS13 Protein Plasma protein binding Molecular Dynamics Simulation 01 natural sciences Article Domain (software engineering) Structure-Activity Relationship 03 medical and health sciences Protein structure 0302 clinical medicine Von Willebrand factor Polysaccharides 0103 physical sciences von Willebrand Factor Disintegrin Humans Protein Interaction Domains and Motifs lcsh:Science Mechanical Phenomena Protein Unfolding 030304 developmental biology Thrombospondin 0303 health sciences Multidisciplinary 010304 chemical physics biology Protein Stability Chemistry lcsh:R ADAMTS13 carbohydrates (lipids) Molecular Docking Simulation 030104 developmental biology biology.protein lcsh:Q 030217 neurology & neurosurgery Protein Binding |
| Zdroj: | Scientific Reports Scientific Reports, Vol 8, Iss 1, Pp 1-11 (2018) |
| ISSN: | 0006-3495 |
| DOI: | 10.1016/j.bpj.2018.11.1054 |
| Popis: | von Willebrand Factor (vWF) is a large multimeric protein that binds to platelets and collagen in blood clotting. vWF A2 domain hosts a proteolytic site for ADAMTS13 (A Disintegrin and Metalloprotease with a ThromboSpondin type 1 motif, member 13) to regulate the size of vWF multimers. This regulation process is highly sensitive to force conditions and protein-glycan interactions as the process occurs in flowing blood. There are two sites on A2 domain (N1515 and N1574) bearing various N-linked glycan structures. In this study, we used molecular dynamics (MD) simulation to study the force-induced unfolding of A2 domain with and without a single N-linked glycan type on each site. The sequential pullout of β-strands was used to represent a characteristic unfolding sequence of A2. This unfolding sequence varied due to protein-glycan interactions. The force-extension and total energy-extension profiles also show differences in magnitude but similar characteristic shapes between the systems with and without glycans. Systems with N-linked glycans encountered higher energy barriers for full unfolding and even for unfolding up to the point of ADAMTS13 cleavage site exposure. Interestingly, there is not much difference observed for A2 domain structure itself with and without glycans from standard MD simulations, suggesting roles of N-glycans in A2 unfolding through long-ranged protein-glycan interactions. |
| Databáze: | OpenAIRE |
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