VDAC1
電壓依賴性陰離子選擇性通道1(VDAC1)是一種β桶蛋白,在人類中是由5號染色體上的VDAC1基因所製造[4][5]。此蛋白質會在線粒體外膜(OMM)和細胞膜中形成離子通道:在OMM上,ATP通過該離子通道而能自線粒體擴散至細胞質;在細胞膜中,VDAC1則參與體積的調節。在所有真核細胞中,線粒體皆負責ATP的合成,並同時合成其他細胞存活所需的代謝物,VDAC1也因而參與線粒體和細胞間的通信,進而調節細胞代謝和死亡之間的平衡。除代謝物的滲透外,VDAC1還可作為己糖激酶等蛋白質的支架,參與代謝過程的調節。[6]
此條目翻譯品質不佳。 (2018年8月15日) |
該蛋白質是電壓依賴性陰離子通道,與其他VDAC同種型(VDAC2和VDAC3)具有高度結構同源性,其參與細胞代謝、線粒體凋亡和精子發生的調節。[7][8][9][10]該通道的過度表達和錯誤調節可導致細胞凋亡,導致體內多種疾病。特別是,由於VDAC1是主要的陰離子離子轉運通道,其功能障礙與癌症,帕金森病(PD)和阿爾茨海默病有關。[11][12][13]
結構
三種VDAC同種型(VDAC1,VDAC2和VDAC3)具有高度保守的DNA序列以及形成寬β-桶結構的3D結構,其中α螺旋N-末端區段駐留以部分閉合通道。[14]VDAC1的結構由3個獨立的實驗室通過X射線晶體學,核磁共振(NMR)光譜學或兩者的組合來解決。這些結構研究中的兩個用於確定人VDAC1(hVDAC1)結構,而X射線晶體學用於解決鼠VDAC1(mVDAC1)結構,其僅與hVDAC1相差僅兩個殘基。[15][16][17]這些確定的結構與先前的圓二色研究一致,該研究預測了α螺旋和β鏈結構域的存在。[18]
mVDAC1的結構分析顯示由19個兩親性β-鏈組成的桶狀通道,其N-末端和C-末端均朝向線粒體的膜間隙。[19][20]β-鏈通過環轉連接並以反平行模式排列,除了平行的β-鏈1和19。[17]通道的高度為40Ẳ,在開口處跨越27Ẳ-20Ẳ的距離,並在打開狀態下在N端α-螺旋段處逐漸減小至20Ẳ×14Ẳ。[21]閉合狀態構象尚未被確定。另外,N-末端具有α螺旋區段,其通過與β-摺疊8-18鏈上的殘基的疏水相互作用而保持在通道的內壁。[17]該N-末端可以用作離子移動或蛋白質附着的支架。一個這樣的例子被看作是HK1結合的位點。[6]要指出的重要殘基是位於氨基酸鏈上第73個殘基的穀氨酸(E73)。該殘基存在於VDAC1和VDAC2中,但不存在於VDAC3中。該帶電殘基的側鏈指向磷脂雙層,這通常會引起排斥力。然而,E73與VDAC1功能和相互作用有關。[22]
功能
VDAC1屬於線粒體孔蛋白家族,並且預測與其他VDAC同種型具有相似的生物學功能。[23]在三種同種型中,VDAC1是主要的鈣離子轉運通道,並且轉錄最多。[12][24]VDAC1通過在線粒體外膜(OMM)上運輸ATP和其他小代謝物參與細胞代謝,從而允許調節TCA循環,並通過延伸,調節活性氧(ROS)的產生。[11]在酵母細胞中,ROS響應於氧化應激而累積,這導致線粒體功能受損和「小」表型。然而,小型酵母細胞表現出比野生型細胞更長的壽命,並且表明VDAC1在例如衰老類似情況下的保護功能。[6][24]
臨床意義
電壓依賴性陰離子通道在離子和代謝物轉運中都起作用,儘管它們的生理作用是不同的。由於它們的作用,通道的功能障礙可導致各種疾病。 VDAC1通過與抗凋亡蛋白家族,Bcl-2蛋白,特別是Bcl-xl和Mcl-1的相互作用而與癌症有關,這些蛋白在癌症過程中過表達。這兩種Bcl-2蛋白與VDAC1相互作用以調節穿過OMM的鈣離子轉運,並最終調節ROS的產生。雖然高水平的ROS誘導細胞死亡,但非致死水平會干擾信號轉導通路,從而促進癌細胞的細胞增殖,遷移和侵襲。[11]此外,VDAC1過表達與增加的凋亡反應和抗癌藥物和治療功效相關,進一步支持VDAC1作為癌症治療的治療靶標。[11][25]
VDAC1在鈣離子轉運中的功能也與神經退行性疾病有關。在PD中,VDAC1增加線粒體內的鈣離子水平,導致線粒體通透性增加,線粒體膜電位破壞,ROS產生增加,細胞死亡和神經元變性。[12]已顯示VDAC1與澱粉樣蛋白β(Aβ)相互作用,導致通道的電導增加並最終導致細胞凋亡。[13]
參考文獻
- ^ 1.0 1.1 1.2 GRCm38: Ensembl release 89: ENSMUSG00000020402 - Ensembl, May 2017
- ^ Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Blachly-Dyson, E.; Baldini, A.; Litt, M.; McCabe, E. R.; Forte, M. Human genes encoding the voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane: mapping and identification of two new isoforms. Genomics. 1994-03-01, 20 (1): 62–67 [2018-08-15]. ISSN 0888-7543. PMID 7517385. doi:10.1006/geno.1994.1127. (原始內容存檔於2018-08-15).
- ^ VDAC1 voltage dependent anion channel 1 [Homo sapiens (human)] - Gene - NCBI. www.ncbi.nlm.nih.gov. [2018-08-15]. (原始內容存檔於2018-08-21).
- ^ 6.0 6.1 6.2 Reina, Simona; Palermo, Vanessa; Guarnera, Andrea; Guarino, Francesca; Messina, Angela; Mazzoni, Cristina; De Pinto, Vito. Swapping of the N-terminus of VDAC1 with VDAC3 restores full activity of the channel and confers anti-aging features to the cell. FEBS letters. 2010-07-02, 584 (13): 2837–2844 [2018-08-15]. ISSN 1873-3468. PMID 20434446. doi:10.1016/j.febslet.2010.04.066. (原始內容存檔於2018-08-15).
- ^ Subedi, Krishna Prasad; Kim, Joon-Chul; Kang, Moonkyung; Son, Min-Jeong; Kim, Yeon-Soo; Woo, Sun-Hee. Voltage-dependent anion channel 2 modulates resting Ca²+ sparks, but not action potential-induced Ca²+ signaling in cardiac myocytes. Cell Calcium. 2011-2, 49 (2): 136–143 [2018-08-15]. ISSN 1532-1991. PMID 21241999. doi:10.1016/j.ceca.2010.12.004. (原始內容存檔於2018-08-21).
- ^ Alvira, Cristina M.; Umesh, Anita; Husted, Cristiana; Ying, Lihua; Hou, Yanli; Lyu, Shu-Chen; Nowak, Jeffrey; Cornfield, David N. Voltage-dependent anion channel-2 interaction with nitric oxide synthase enhances pulmonary artery endothelial cell nitric oxide production. American Journal of Respiratory Cell and Molecular Biology. 2012-11, 47 (5): 669–678 [2018-08-15]. ISSN 1535-4989. PMC 3547107 . PMID 22842492. doi:10.1165/rcmb.2011-0436OC. (原始內容存檔於2018-08-15).
- ^ Cheng, Emily H. Y.; Sheiko, Tatiana V.; Fisher, Jill K.; Craigen, William J.; Korsmeyer, Stanley J. VDAC2 inhibits BAK activation and mitochondrial apoptosis. Science (New York, N.Y.). 2003-07-25, 301 (5632): 513–517 [2018-08-15]. ISSN 1095-9203. PMID 12881569. doi:10.1126/science.1083995. (原始內容存檔於2018-08-21).
- ^ Li, Zhonghua; Wang, Yongqiang; Xue, Yanfei; Li, Xiaoqi; Cao, Hong; Zheng, Shijun J. Critical Role for Voltage-Dependent Anion Channel 2 in Infectious Bursal Disease Virus-Induced Apoptosis in Host Cells via Interaction with VP5. Journal of Virology. 2012-2, 86 (3): 1328–1338. ISSN 0022-538X. PMC 3264341 . PMID 22114330. doi:10.1128/JVI.06104-11.
- ^ 11.0 11.1 11.2 11.3 Huang, H; Shah, K; Bradbury, N A; Li, C; White, C. Mcl-1 promotes lung cancer cell migration by directly interacting with VDAC to increase mitochondrial Ca2+ uptake and reactive oxygen species generation. Cell Death & Disease. 2014-10, 5 (10): e1482. ISSN 2041-4889. PMC 4237246 . PMID 25341036. doi:10.1038/cddis.2014.419.
- ^ 12.0 12.1 12.2 Chu, Yaping; Goldman, Jennifer G.; Kelly, Leo; He, Yinzhen; Waliczek, Tracy; Kordower, Jeffrey H. Abnormal alpha-synuclein reduces nigral voltage-dependent anion channel 1 in sporadic and experimental Parkinson's disease. Neurobiology of Disease. 2014-09, 69: 1–14 [2018-08-15]. ISSN 0969-9961. doi:10.1016/j.nbd.2014.05.003. (原始內容存檔於2022-03-20).
- ^ 13.0 13.1 Smilansky, Angela; Dangoor, Liron; Nakdimon, Itay; Ben-Hail, Danya; Mizrachi, Dario; Shoshan-Barmatz, Varda. The Voltage-dependent Anion Channel 1 Mediates Amyloid β Toxicity and Represents a Potential Target for Alzheimer Disease Therapy. The Journal of Biological Chemistry. 2015-12-25, 290 (52): 30670–30683. ISSN 0021-9258. PMC 4692199 . PMID 26542804. doi:10.1074/jbc.M115.691493.
- ^ Amodeo, Giuseppe Federico; Scorciapino, Mariano Andrea; Messina, Angela; De Pinto, Vito; Ceccarelli, Matteo. Charged Residues Distribution Modulates Selectivity of the Open State of Human Isoforms of the Voltage Dependent Anion-Selective Channel. PLoS ONE. 2014-08-01, 9 (8). ISSN 1932-6203. PMC 4146382 . PMID 25084457. doi:10.1371/journal.pone.0103879.
- ^ Bayrhuber, Monika; Meins, Thomas; Habeck, Michael; Becker, Stefan; Giller, Karin; Villinger, Saskia; Vonrhein, Clemens; Griesinger, Christian; Zweckstetter, Markus. Structure of the human voltage-dependent anion channel. Proceedings of the National Academy of Sciences of the United States of America. 2008-10-07, 105 (40): 15370–15375. ISSN 0027-8424. PMC 2557026 . PMID 18832158. doi:10.1073/pnas.0808115105.
- ^ Hiller, Sebastian; Garces, Robert G.; Malia, Thomas J.; Orekhov, Vladislav Y.; Colombini, Marco; Wagner, Gerhard. Solution structure of the integral human membrane protein VDAC-1 in detergent micelles. Science (New York, N.Y.). 2008-08-29, 321 (5893): 1206–1210. ISSN 0036-8075. PMC 2579273 . PMID 18755977. doi:10.1126/science.1161302.
- ^ 17.0 17.1 17.2 Ujwal, Rachna; Cascio, Duilio; Colletier, Jacques-Philippe; Faham, Salem; Zhang, Jun; Toro, Ligia; Ping, Peipei; Abramson, Jeff. The crystal structure of mouse VDAC1 at 2.3 Å resolution reveals mechanistic insights into metabolite gating. Proceedings of the National Academy of Sciences of the United States of America. 2008-11-18, 105 (46): 17742–17747. ISSN 0027-8424. PMC 2584669 . PMID 18988731. doi:10.1073/pnas.0809634105.
- ^ Shanmugavadivu, Baladhandapani; Apell, Hans-Jürgen; Meins, Thomas; Zeth, Kornelius; Kleinschmidt, Jörg H. Correct Folding of the β-Barrel of the Human Membrane Protein VDAC Requires a Lipid Bilayer. Journal of Molecular Biology. 2007-04, 368 (1): 66–78 [2018-08-15]. ISSN 0022-2836. doi:10.1016/j.jmb.2007.01.066. (原始內容存檔於2021-05-25).
- ^ McCommis, Kyle S.; Baines, Christopher P. The Role of VDAC in Cell Death: Friend or Foe?. Biochimica et Biophysica Acta. 2012-6, 1818 (6): 1444–1450. ISSN 0006-3002. PMC 3288473 . PMID 22062421. doi:10.1016/j.bbamem.2011.10.025.
- ^ Tomasello, Marianna F.; Guarino, Francesca; Reina, Simona; Messina, Angela; De Pinto, Vito. The Voltage-Dependent Anion Selective Channel 1 (VDAC1) Topography in the Mitochondrial Outer Membrane as Detected in Intact Cell. PLoS ONE. 2013-12-06, 8 (12) [2018-08-15]. ISSN 1932-6203. PMC 3855671 . PMID 24324700. doi:10.1371/journal.pone.0081522. (原始內容存檔於2022-04-02).
- ^ Teijido, Oscar; Ujwal, Rachna; Hillerdal, Carl-Olof; Kullman, Lisen; Rostovtseva, Tatiana K.; Abramson, Jeff. Affixing N-terminal α-Helix to the Wall of the Voltage-dependent Anion Channel Does Not Prevent Its Voltage Gating. The Journal of Biological Chemistry. 2012-03-30, 287 (14): 11437–11445. ISSN 0021-9258. PMC 3322836 . PMID 22275367. doi:10.1074/jbc.M111.314229.
- ^ Keinan, Nurit; Pahima, Hadas; Ben-Hail, Danya; Shoshan-Barmatz, Varda. The role of calcium in VDAC1 oligomerization and mitochondria-mediated apoptosis. Biochimica Et Biophysica Acta. 2013-7, 1833 (7): 1745–1754 [2018-08-15]. ISSN 0006-3002. PMID 23542128. doi:10.1016/j.bbamcr.2013.03.017. (原始內容存檔於2018-08-21).
- ^ Lee, Mi-Jung; Kim, Jee-Youn; Suk, Kyoungho; Park, Jae-Hoon. Identification of the Hypoxia-Inducible Factor 1α-Responsive HGTD-P Gene as a Mediator in the Mitochondrial Apoptotic Pathway. Molecular and Cellular Biology. 2004-5, 24 (9): 3918–3927. ISSN 0270-7306. PMC 387743 . PMID 15082785. doi:10.1128/MCB.24.9.3918-3927.2004.
- ^ 24.0 24.1 De Pinto, Vito; Guarino, Francesca; Guarnera, Andrea; Messina, Angela; Reina, Simona; Tomasello, Flora M.; Palermo, Vanessa; Mazzoni, Cristina. Characterization of human VDAC isoforms: a peculiar function for VDAC3?. Biochimica Et Biophysica Acta. 2010-6, 1797 (6-7): 1268–1275 [2018-08-15]. ISSN 0006-3002. PMID 20138821. doi:10.1016/j.bbabio.2010.01.031. (原始內容存檔於2018-08-21).
- ^ Weisthal, Shira; Keinan, Nurit; Ben-Hail, Danya; Arif, Tasleem; Shoshan-Barmatz, Varda. Ca(2+)-mediated regulation of VDAC1 expression levels is associated with cell death induction. Biochimica Et Biophysica Acta. 2014-10, 1843 (10): 2270–2281 [2018-08-15]. ISSN 0006-3002. PMID 24704533. doi:10.1016/j.bbamcr.2014.03.021. (原始內容存檔於2018-08-15).