Structural basis of dysfunctional apolipoprotein-induced dyslipidemia

2012 Fiscal Year Final Research Report

• Project/Area Number: 22590046
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Physical pharmacy
• Research Institution: The University of Tokushima
• Principal Investigator: SAITO Hiroyuki 徳島大学, 大学院・ヘルスバイオサイエンス研究部, 教授 (60300919)
• Co-Investigator(Renkei-kenkyūsha): TANAKA Masafumi 神戸薬科大学, 薬学部, 講師 (40411904)
• Project Period (FY): 2010 – 2012
• Keywords: 脂質異常症 / アミロイドーシス / リポタンパク質 / アポリポタンパク質 / フォールディング構造異常

Research Abstract

To probe the structural effects of naturally occurring mutations of apolipoproteins that lead to hypolipoproteinemia and systemic amyloidosis, we examined the tertiary structure, stability, lipid-binding property, and aggregation propensity of apolipoprotein A-I and E variants. The results indicate that the disruption of the N-terminal helix bundle and the C-terminal helical structure in apolipoproteins caused by the mutations leads to the critical outcomes of diseases.

Research Products

• [Journal Article] Slow Tumbling but Large Protrusion of Phospholipids in the Cell Sized Giant Vesicle. (2013)
  • Author(s): Takechi, Y., Saito, H., and Okamura, E
  • Journal Title: Chem. Phys. Lett Volume: 570 Pages: 136-140
  • DOI: DOI:http://dx.doi.org/10.1016/j.cplett.2013.03.048
  • Peer Reviewed
• [Journal Article] Interactions of Apolipoprotein A-I with High Density Lipoprotein Particles (2013)
  • Author(s): Nguyen, D., Nickel, M., Mizuguchi, C., Saito, H., Lund-Katz, S., and Phillips, M. C
  • Journal Title: Biochemistry Volume: 52(11) Pages: 1963-1972
  • DOI: DOI:10.1021/bi400032y
  • Peer Reviewed
• [Journal Article] Effect of Amino Acid Distribution of Amphipathic Helical Peptide Derived from Human Apolipoprotein A-I on Membrane Curvature Sensing. (2013)
  • Author(s): Tanaka, M., Takamura, Y., Kawakami, T., Aimoto, S., Saito, H., and Mukai, T
  • Journal Title: FEBS Lett Volume: 587(5) Pages: 510-515
  • DOI: DOI:10.1016/j.febslet.2013.01.026
  • Peer Reviewed
• [Journal Article] Dual Role of an N-terminal Amyloidogenic Mutation in Apolipoprotein A-I: Destabilization of Helix Bundle and Enhancement of Fibril Formation (2013)
  • Author(s): Adachi, E., Nakajima, H., Mizuguchi, C., Dhanasekaran, P., Kawashima, H., Nagao, K., Akaji, K., Lund-Katz, S., Phillips, M. C., and Saito, H
  • Journal Title: J. Biol. Chem Volume: 288(4) Pages: 2848-2856
  • DOI: DOI:10.1074/jbc.M112.428052
  • Peer Reviewed
• [Journal Article] Effects of the Iowa and Milano Mutations on Apolipoprotein A-I Structure and Dynamics Determined by Hydrogen Exchange and Mass Spectrometry (2012)
  • Author(s): Chetty, P. S., Ohshiro, M., Saito, H., Dhanasekaran, P., Lund-Katz, S., Mayne, L., Englander, W., and Phillips, M. C
  • Journal Title: Biochemistry Volume: 51(44) Pages: 8993-9001
  • DOI: DOI:10.1021/bi300926j
  • Peer Reviewed
• [Journal Article] Physicochemical Mechanism for the Lipid Membrane Binding of Polyarginine: the Favorable Enthalpy Change with Structural Transition from Random Coil to α-Helix (2012)
  • Author(s): Takechi, Y., Mizuguchi, C., Tanaka, M., Kawakami, T., Aimoto, S., Okamura, E., and Saito, H
  • Journal Title: Chem. Lett Volume: 41(10) Pages: 1374-1376
  • DOI: DOI:10.1246/cl.2012.1374
  • Peer Reviewed
• [Journal Article] Fluorescence Analysis of the Lipid Binding-induced Conformational Change of Apolipoprotein E4 (2012)
  • Author(s): Mizuguchi, C., Hata, M., Dhanasekaran, P.,Nickel, M., Phillips, M. C., Lund-Katz, S., and Saito, H
  • Journal Title: Biochemistry Volume: 51(28) Pages: 5580-5588
  • DOI: DOI:10.1021/bi300672s
  • Peer Reviewed
• [Journal Article] Influence of C-Terminal α-Helix Hydrophobicity and Aromatic Amino Acid Content on Apolipoprotein A-I Functionality. (2012)
  • Author(s): Lyssenko, N. N., Hata, M., Dhanasekaran, P., Nickel, M., Chetty, P. S., Saito, H., Lund-KatzS., and Phillips, M. C
  • Journal Title: Biochim. Biophys. Acta-Mol. Cell Biol. Lipids Volume: 1821(3) Pages: 456-463
  • DOI: DOI:10.1016/j.bbalip.2011.07.020
  • Peer Reviewed
• [Journal Article] Comparative Study on the Interaction of Cell-Penetrating Polycationic Polymers with Lipid Membranes (2012)
  • Author(s): Takechi, Y., Tanaka, H., Kitayama, H., Yoshii, H., Tanaka, M., and Saito, H
  • Journal Title: Chem. Phys. Lipids Volume: 165(1) Pages: 51-58
  • DOI: DOI:10.1016/j.chemphyslip.2011.11.002
  • Peer Reviewed
• [Journal Article] Identification of Regions Responsible for Heparin-Induced Amyloidogenesis of Human Serum Amyloid A Using Its Fragment Peptides. (2011)
  • Author(s): Egashira, M., Takase, H., Yamamoto, I., Tanaka, M., and Saito, H
  • Journal Title: Arch. Biochem. Biophys Volume: 511(1-2) Pages: 101-106
  • DOI: DOI:10.1016/j.abb.2011.04.019
  • Peer Reviewed
• [Journal Article] Physicochemical Mechanism for the Enhanced Ability of Lipid Membrane Penetration of Polyarginine (2011)
  • Author(s): Takechi, Y., Yoshii, H., Tanaka, M., Kawakami, T., Aimoto, S., and Saito, H
  • Journal Title: Langmuir Volume: 27(11) Pages: 7099-7107
  • DOI: DOI:10.1021/la200917y
  • Peer Reviewed
• [Journal Article] Influence of N-Terminal Helix Bundle Stability on the Lipid-Binding Properties of Human Apolipoprotein A-I. (2011)
  • Author(s): Tanaka, M., Dhanasekaran, P., Nguyen, D., Nickel, M., Takechi, Y., Lund-Katz, S., Phillips, M. C., and Saito, H
  • Journal Title: Biochim. Biophys. Acta-Mol. Cell Biol. Lipids Volume: 1811(1) Pages: 25-30
  • DOI: DOI:10.1016/j.bbalip.2010.10.003
  • Peer Reviewed
• [Journal Article] Molecular Basis for the Differences in Lipid and Lipoprotein Binding Properties of Human Apolipoproteins E3 and E4 (2010)
  • Author(s): Nguyen, D., Dhanasekaran, P., Nickel, M., Nakatani, R., Saito, H., Phillips, M. C., and Lund-Katz, S
  • Journal Title: Biochemistry Volume: 49(51) Pages: 10881-10889
  • DOI: DOI:10.1021/bi1017655
  • Peer Reviewed
• [Journal Article] Disruption of the C-terminal Helix by Single Amino Acid Deletion is Directly Responsible for Impaired Cholesterol Efflux Ability of Apolipoprotein A-I Nichinan. (2010)
  • Author(s): Kono, M., Tanaka, T., Tanaka, M., Vedhachalam, C., Chetty, P. S., Nguyen, D., Dhanasekaran, P., Lund-Katz, S., Phillips, M. C., and Saito, H
  • Journal Title: J. Lipid Res Volume: 51(4) Pages: 809-818
  • DOI: DOI:10.1194/jlr.M002113
  • Peer Reviewed
• [Journal Article] Surface Plasmon Resonance Analysis of the Mechanism of Binding of ApoA-I to High Density Lipoprotein Particles. (2010)
  • Author(s): Lund-Katz, S., Nguyen, D., Dhanasekaran, P., Kono, M., Nickel, M., Saito, H., and Phillips, M. C
  • Journal Title: J. Lipid Res Volume: 51(3) Pages: 606-617
  • DOI: DOI:10.1194/jlr.M002055
  • Peer Reviewed
• [Presentation] アミロイド-シス変異アポA-Iの線維形成と細胞増殖抑制作用 (2013)
  • Author(s): 中嶋 宏之
  • Organizer: 日本薬学会第133 年会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2013-03-29
• [Presentation] Physicochemical Mechanism for the Enhanced Ability of Lipid Membrane Penetration of Polyarginine (2012)
  • Author(s): Takechi, Y., Yoshii, H., Tanaka, M., Kawakami, T., Aimoto, S., Okamura, E., Saito, H
  • Organizer: International Association of Colloid and Interface Scientists 2012
  • Place of Presentation: 仙台国際センター,宮城県
  • Year and Date: 20120513-18
• [Presentation] Interactions of apoA-I with HDL particles (2012)
  • Author(s): Lund-Katz, S., Nguyen, D., Dhanasekaran, P., Nickel, M., Hata, M., Saito, H., Phillips, M. C
  • Organizer: XVI International Symposium on Atherosclerosis HDL Satellite Meeting
  • Place of Presentation: Hilton Cairns, Cairns, Australia
  • Year and Date: 20120330-0401
• [Presentation] 細胞サイズベシクルの高濃度調製と溶液 NMR による物性解析 (2012)
  • Author(s): 武知 佑樹
  • Organizer: 第34回生体膜と薬物の相互作用シンポジウム
  • Place of Presentation: 京都大学(京都府)
  • Year and Date: 2012-11-16
• [Presentation] HDL 形成過程におけるABCA1 トランスポーターと apoA-I の結合機構の解析 (2012)
  • Author(s): 長尾 耕治郎
  • Organizer: 第34回生体膜と薬物の相互作用シンポジウム
  • Place of Presentation: 京都大学(京都府)
  • Year and Date: 2012-11-16
• [Presentation] ABCA1 と apoA-I の結合機構の解析 (2012)
  • Author(s): 長尾 耕治郎
  • Organizer: 膜シンポジウム 2012
  • Place of Presentation: 神戸大学(兵庫県)
  • Year and Date: 2012-11-07
• [Presentation] 溶液 NMR を用いた細胞サイズベシクルの評価 (2012)
  • Author(s): 武知 佑樹
  • Organizer: 膜シンポジウム 2012
  • Place of Presentation: 膜シンポジウム 2012
  • Year and Date: 2012-11-06
• [Presentation] 脂質結合タンパク質アポ A-Iの G26R 変異によるアミロイド線維形成 (2012)
  • Author(s): 足立 愛美
  • Organizer: 膜シンポジウム 2012
  • Place of Presentation: 神戸大学(兵庫県)
  • Year and Date: 2012-11-06
• [Presentation] Membrane disc formation from tetraether-type artificial phospholipids and apolipoproteins (2012)
  • Author(s): 馬場 照彦
  • Organizer: 第50回日本生物物理学会年会
  • Place of Presentation: 名古屋大学(愛知県)
  • Year and Date: 2012-09-22
• [Presentation] 部分フッ素化リン脂質と脂質親和性タンパク質からの膜ディスク形成 (2012)
  • Author(s): 馬場 照彦
  • Organizer: 日本膜学会第34 年会
  • Place of Presentation: 早稲田大学(東京都)
  • Year and Date: 2012-05-08
• [Presentation] ApoA-I Iowa (G26R) 変異によるアミロイド線維形成 (2012)
  • Author(s): 足立 愛美
  • Organizer: 日本膜学会第34 年会
  • Place of Presentation: 早稲田大学(東京都)
  • Year and Date: 2012-05-08
• [Presentation] ヒト血清アミロイドA(SAA)の中間領域の線維形成能評価 (2012)
  • Author(s): 高瀬 ひろか
  • Organizer: 日本薬学会第132 年会
  • Place of Presentation: 北海道大学(北海道)
  • Year and Date: 2012-03-30
• [Presentation] 分枝鎖人工リン脂質とアポリポタンパク質 A-I からの膜ディスク形成 (2012)
  • Author(s): 馬場 照彦
  • Organizer: 日本化学会第92 春季年会
  • Place of Presentation: 慶應義塾大学(神奈川県)
  • Year and Date: 2012-03-27
• [Presentation] Amide hydrogen-deuterium exchange as a tool to probe the effects of point-mutations on apolipoprotein A-I structure-function (2011)
  • Author(s): Chetty, P. S., Takase, H., Saito, H., Lund-Katz, S., Mayne, L., Englander, W., Phillips, M. C
  • Organizer: Arteriosclerosis, Thrombosis and Vascular Biology 2011
  • Place of Presentation: Hilton Chicago, Chicago, USA
  • Year and Date: 20110428-30
• [Presentation] 環境感受性蛍光プローブ標識によるアポ E コンフォメーション変化の解析 (2011)
  • Author(s): 中谷 亮介
  • Organizer: 第33回生体膜と薬物の相互作用シンポジウム
  • Place of Presentation: 岡山大学(岡山県)
  • Year and Date: 2011-11-24
• [Presentation] アポ A-I アミロイドーシス変異体の物性とアミロイド形成の評価 (2011)
  • Author(s): 足立 愛美
  • Organizer: 第50回日本薬学会中国四国支部学術大会
  • Place of Presentation: サンポート高松(香川県)
  • Year and Date: 2011-11-12
• [Presentation] 硫酸化度の異なるグリコサミノグリカンがヒト血清アミロイドAの線維形成に与える影響 (2011)
  • Author(s): 高瀬 ひろか
  • Organizer: 第61回日本薬学会近畿支部大会
  • Place of Presentation: 神戸学院大学(兵庫県)
  • Year and Date: 2011-10-22
• [Presentation] グリコサミノグリカンによるヒト血清アミロイド A の線維形成部位の検討 (2011)
  • Author(s): 高瀬 ひろか
  • Organizer: 第84回日本生化学大会
  • Place of Presentation: 京都国際会議場(京都府)
  • Year and Date: 2011-09-22
• [Presentation] テトラエーテル型リン脂質類縁体の膜特性と脂質親和性タンパク質との複合体形成 (2011)
  • Author(s): 馬場 照彦
  • Organizer: 日本膜学会第33 年会
  • Place of Presentation: 産総研臨海副都心センター(東京都)
  • Year and Date: 2011-05-12
• [Presentation] 両親媒性ペプチドの膜曲率認識におけるアミノ酸置換の影響 (2011)
  • Author(s): 田中 将史
  • Organizer: 日本膜学会第33 年会
  • Place of Presentation: 産総研臨海副都心センター(東京都)
  • Year and Date: 2011-05-12
• [Presentation] 膜透過性アルギニンポリペプチドと酸性リン脂質膜の相互作用 (2011)
  • Author(s): 武知 佑樹
  • Organizer: 日本膜学会第33 年会
  • Place of Presentation: 産総研臨海副都心センター(東京都)
  • Year and Date: 2011-05-12
• [Presentation] 膜曲率センサーとして働くアポ A-I の構造要件の検討 (2011)
  • Author(s): 田中 将史
  • Organizer: 日本薬学会第131 年会
  • Place of Presentation: グランシップ静岡(静岡県)
  • Year and Date: 2011-03-30
• [Presentation] 安定膜形成性人工リン脂質とアポリポタンパク質 A-I からの膜ディスク形成とその安定性 (2011)
  • Author(s): 馬場 照彦
  • Organizer: 日本化学会第91 春季年会
  • Place of Presentation: 神奈川大学(神奈川県)
  • Year and Date: 2011-03-28
• [Presentation] Effect of amino acid residues on membrane curvature sensing of amphipathic helix in human apolipoprotein A-I (2010)
  • Author(s): Tanaka, M., Takamura, Y., Kawakami, T., Aimoto, S., Saito, H
  • Organizer: 5th International Peptide Symposium
  • Place of Presentation: 京都国際会議場,京都府
  • Year and Date: 20101204-09
• [Presentation] Interactions of apolipoprotein A-I with spherical HDL particles (2010)
  • Author(s): Lund-Katz, S., Nguyen, D., Dhanasekaran, P., Kono, M., Nickel, M., Saito, H., Phillips, M. C
  • Organizer: 6thIAS-sponsored Workshop on HDL
  • Place of Presentation: Westin Whistler, Whistler, Canada
  • Year and Date: 20100517-20
• [Presentation] 細胞膜透過ペプチドの物理的膜透過メカニズム解明に向けたアルギニンポリペプチド-脂質二分子膜間相互作用の解析 (2010)
  • Author(s): 武知 佑樹
  • Organizer: 第32回生体膜と薬物の相互作用シンポジウム
  • Place of Presentation: 富山国際会議場(富山県)
  • Year and Date: 2010-11-29
• [Presentation] 疎水性アミノ酸残基を持つカチオン性コポリペプチドと脂質二分子膜との相互作用 (2010)
  • Author(s): 植野 哲
  • Organizer: 膜シンポジウム 2010
  • Place of Presentation: 京都大学(京都府)
  • Year and Date: 2010-11-19
• [Presentation] ApoA-I Nichinan (ΔE235) 変異による HDL 粒子形成異常のメカニズム (2010)
  • Author(s): 河野 百恵
  • Organizer: 日本膜学会第32 年会
  • Place of Presentation: 産総研臨海副都心センター(東京都)
  • Year and Date: 2010-05-14
• [Presentation] フラグメントペプチドを用いた血清アミロイド A 蛋白(SAA)アミロイド化部位の探索 (2010)
  • Author(s): 江頭 昌志
  • Organizer: 日本膜学会第32 年会
  • Place of Presentation: 産総研臨海副都心センター(東京都)
  • Year and Date: 2010-05-14
• [Book] 製剤への物理化学 第2版 (2012)
  • Author(s): 斎藤 博幸,他
  • Total Pages: 302
  • Publisher: 廣川書店