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Open AccessArticle

Nrp1 is Activated by Konjac Ceramide Binding-Induced Structural Rigidification of the a1a2 Domain

1
Lipid Biofunction Section, Faculty of Advanced Life Science, Hokkaido University, Sapporo 001-0021, Hokkaido, Japan
2
Bioproduction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Sapporo 062-8517, Hokkaido, Japan
3
Computational Bio Big-Data Open Innovation Laboratory (CBBD-OIL), AIST, Tokyo 169-8555, Japan
4
Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Aomori, Japan
5
Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Hokkaido University of Science, Sapporo 006-8585, Hokkaido, Japan
6
Faculty of Advanced Life Science, Hokkaido University, Sapporo 001-0021, Hokkaido, Japan
7
R&D Headquarters, Daicel Corporation, Tokyo 108-8230, Japan
*
Author to whom correspondence should be addressed.
Cells 2020, 9(2), 517; https://doi.org/10.3390/cells9020517
Received: 19 January 2020 / Revised: 14 February 2020 / Accepted: 19 February 2020 / Published: 24 February 2020
(This article belongs to the Special Issue Sphingolipids in Cancer Progression and Therapy)
Konjac ceramide (kCer) is a plant-type ceramide composed of various long-chain bases and α-hydroxyl fatty acids. The presence of d4t,8t-sphingadienine is essential for semaphorin 3A (Sema3A)-like activity. Herein, we examined the three neuropilin 1 (Nrp1) domains (a1a2, b1b2, or c), and found that a1a2 binds to d4t,8t-kCer and possesses Sema3A-like activity. kCer binds to Nrp1 with a weak affinity of μM dissociation constant (Kd). We wondered whether bovine serum albumin could influence the ligand–receptor interaction that a1a2 has with a single high affinity binding site for kCer (Kd in nM range). In the present study we demonstrated the influence of bovine serum albumin. Thermal denaturation indicates that the a1a2 domain may include intrinsically disordered region (IDR)-like flexibility. A potential interaction site on the a1 module was explored by molecular docking, which revealed a possible Nrp1 activation mechanism, in which kCer binds to Site A close to the Sema3A-binding region of the a1a2 domain. The a1 module then accesses a2 as the IDR-like flexibility becomes ordered via kCer-induced protein rigidity of a1a2. This induces intramolecular interaction between a1 and a2 through a slight change in protein secondary structure. View Full-Text
Keywords: ceramide; konjac; semaphorin3A; neurite outgrowth; neuropilin 1; endoglycoceramidase; sphingadienine ceramide; konjac; semaphorin3A; neurite outgrowth; neuropilin 1; endoglycoceramidase; sphingadienine
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Usuki, S.; Yasutake, Y.; Tamura, N.; Tamura, T.; Tanji, K.; Saitoh, T.; Murai, Y.; Mikami, D.; Yuyama, K.; Monde, K.; Mukai, K.; Igarashi, Y. Nrp1 is Activated by Konjac Ceramide Binding-Induced Structural Rigidification of the a1a2 Domain. Cells 2020, 9, 517.

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