imported>InternetArchiveBot：补救12个来源，并将0个来源标记为失效。) #IABot (v2.0.8.7

2022-05-18T12:38:36Z

补救12个来源，并将0个来源标记为失效。) #IABot (v2.0.8.7

新页面

{{Infobox_gene}}
{{roughtranslation|time=2018-08-15T15:19:42+00:00}}
'''电压依赖性阴离子选择性通道1'''（'''VDAC1'''）是一种β桶蛋白，在人类中是由[[5号染色体 (人类)|5号染色体]]上的''VDAC1''基因所製造<ref>{{Cite journal|title=Human genes encoding the voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane: mapping and identification of two new isoforms|url=https://www.ncbi.nlm.nih.gov/pubmed/7517385|last=Blachly-Dyson|first=E.|last2=Baldini|first2=A.|date=1994-03-01|journal=Genomics|issue=1|doi=10.1006/geno.1994.1127|volume=20|pages=62–67|issn=0888-7543|pmid=7517385|last3=Litt|first3=M.|last4=McCabe|first4=E. R.|last5=Forte|first5=M.|access-date=2018-08-15|archive-date=2018-08-15|archive-url=https://web.archive.org/web/20180815201826/https://www.ncbi.nlm.nih.gov/pubmed/7517385}}</ref><ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=7416|title=VDAC1 voltage dependent anion channel 1 [Homo sapiens (human)] - Gene - NCBI|accessdate=2018-08-15|work=www.ncbi.nlm.nih.gov|archive-date=2018-08-21|archive-url=https://web.archive.org/web/20180821124412/https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=7416}}</ref>。此蛋白質會在[[线粒体外膜]]（OMM）和[[细胞膜]]中形成[[离子通道]]：在OMM上，[[三磷酸腺苷|ATP]]通過該離子通道而能自线粒体扩散至细胞质；在细胞膜中，VDAC1則参与体积的调节。在所有真核细胞中，线粒体皆負責ATP的合成，並同時合成其他细胞存活所需的代谢物，VDAC1也因而參與线粒体和细胞间的通信，進而調節细胞代谢和死亡之间的平衡。除代谢物的渗透外，VDAC1还可作为[[己糖激酶]]等蛋白质的支架，參與代謝過程的調節。<ref name=":0">{{Cite journal|title=Swapping of the N-terminus of VDAC1 with VDAC3 restores full activity of the channel and confers anti-aging features to the cell|url=https://www.ncbi.nlm.nih.gov/pubmed/20434446|last=Reina|first=Simona|last2=Palermo|first2=Vanessa|date=2010-07-02|journal=FEBS letters|issue=13|doi=10.1016/j.febslet.2010.04.066|volume=584|pages=2837–2844|issn=1873-3468|pmid=20434446|last3=Guarnera|first3=Andrea|last4=Guarino|first4=Francesca|last5=Messina|first5=Angela|last6=Mazzoni|first6=Cristina|last7=De Pinto|first7=Vito|access-date=2018-08-15|archive-date=2018-08-15|archive-url=https://web.archive.org/web/20180815201844/https://www.ncbi.nlm.nih.gov/pubmed/20434446}}</ref>

该蛋白质是[[电压依赖性阴离子通道]]，与其他VDAC同种型（[[VDAC2]]和[[VDAC3]]）具有高度结构同源性，其参与[[细胞代谢]]、[[线粒体凋亡]]和精子发生的调节。<ref>{{Cite journal|title=Voltage-dependent anion channel 2 modulates resting Ca²+ sparks, but not action potential-induced Ca²+ signaling in cardiac myocytes|url=https://www.ncbi.nlm.nih.gov/pubmed/21241999|last=Subedi|first=Krishna Prasad|last2=Kim|first2=Joon-Chul|date=2011-2|journal=Cell Calcium|issue=2|doi=10.1016/j.ceca.2010.12.004|volume=49|pages=136–143|issn=1532-1991|pmid=21241999|last3=Kang|first3=Moonkyung|last4=Son|first4=Min-Jeong|last5=Kim|first5=Yeon-Soo|last6=Woo|first6=Sun-Hee|access-date=2018-08-15|archive-date=2018-08-21|archive-url=https://web.archive.org/web/20180821124510/https://www.ncbi.nlm.nih.gov/pubmed/21241999}}</ref><ref>{{Cite journal|title=Voltage-dependent anion channel-2 interaction with nitric oxide synthase enhances pulmonary artery endothelial cell nitric oxide production|url=https://www.ncbi.nlm.nih.gov/pubmed/22842492|last=Alvira|first=Cristina M.|last2=Umesh|first2=Anita|date=2012-11|journal=American Journal of Respiratory Cell and Molecular Biology|issue=5|doi=10.1165/rcmb.2011-0436OC|volume=47|pages=669–678|issn=1535-4989|pmc=3547107|pmid=22842492|last3=Husted|first3=Cristiana|last4=Ying|first4=Lihua|last5=Hou|first5=Yanli|last6=Lyu|first6=Shu-Chen|last7=Nowak|first7=Jeffrey|last8=Cornfield|first8=David N.|access-date=2018-08-15|archive-date=2018-08-15|archive-url=https://web.archive.org/web/20180815164618/https://www.ncbi.nlm.nih.gov/pubmed/22842492}}</ref><ref>{{Cite journal|title=VDAC2 inhibits BAK activation and mitochondrial apoptosis|url=https://www.ncbi.nlm.nih.gov/pubmed/12881569|last=Cheng|first=Emily H. Y.|last2=Sheiko|first2=Tatiana V.|date=2003-07-25|journal=Science (New York, N.Y.)|issue=5632|doi=10.1126/science.1083995|volume=301|pages=513–517|issn=1095-9203|pmid=12881569|last3=Fisher|first3=Jill K.|last4=Craigen|first4=William J.|last5=Korsmeyer|first5=Stanley J.|access-date=2018-08-15|archive-date=2018-08-21|archive-url=https://web.archive.org/web/20180821124426/https://www.ncbi.nlm.nih.gov/pubmed/12881569}}</ref><ref>{{Cite journal|title=Critical Role for Voltage-Dependent Anion Channel 2 in Infectious Bursal Disease Virus-Induced Apoptosis in Host Cells via Interaction with VP5|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3264341/|last=Li|first=Zhonghua|last2=Wang|first2=Yongqiang|date=2012-2|journal=Journal of Virology|issue=3|doi=10.1128/JVI.06104-11|volume=86|pages=1328–1338|issn=0022-538X|pmc=3264341|pmid=22114330|last3=Xue|first3=Yanfei|last4=Li|first4=Xiaoqi|last5=Cao|first5=Hong|last6=Zheng|first6=Shijun J.}}</ref>该通道的过度表达和错误调节可导致细胞凋亡，导致体内多种疾病。特别是，由于VDAC1是主要的阴离子离子转运通道，其功能障碍与癌症，[[帕金森氏症|帕金森病]]（PD）和[[阿茲海默症|阿尔茨海默病]]有关。<ref name=":1">{{Cite journal|title=Mcl-1 promotes lung cancer cell migration by directly interacting with VDAC to increase mitochondrial Ca2+ uptake and reactive oxygen species generation|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237246/|last=Huang|first=H|last2=Shah|first2=K|date=2014-10|journal=Cell Death & Disease|issue=10|doi=10.1038/cddis.2014.419|volume=5|pages=e1482|issn=2041-4889|pmc=4237246|pmid=25341036|last3=Bradbury|first3=N A|last4=Li|first4=C|last5=White|first5=C}}</ref><ref name=":2">{{Cite journal|title=Abnormal alpha-synuclein reduces nigral voltage-dependent anion channel 1 in sporadic and experimental Parkinson's disease|url=http://linkinghub.elsevier.com/retrieve/pii/S0969996114001132|last=Chu|first=Yaping|last2=Goldman|first2=Jennifer G.|date=2014-09|journal=Neurobiology of Disease|doi=10.1016/j.nbd.2014.05.003|volume=69|pages=1–14|issn=0969-9961|last3=Kelly|first3=Leo|last4=He|first4=Yinzhen|last5=Waliczek|first5=Tracy|last6=Kordower|first6=Jeffrey H.|access-date=2018-08-15|archive-date=2022-03-20|archive-url=https://web.archive.org/web/20220320033626/https://linkinghub.elsevier.com/retrieve/pii/S0969996114001132}}</ref><ref name=":3">{{Cite journal|title=The Voltage-dependent Anion Channel 1 Mediates Amyloid β Toxicity and Represents a Potential Target for Alzheimer Disease Therapy|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4692199/|last=Smilansky|first=Angela|last2=Dangoor|first2=Liron|date=2015-12-25|journal=The Journal of Biological Chemistry|issue=52|doi=10.1074/jbc.M115.691493|volume=290|pages=30670–30683|issn=0021-9258|pmc=4692199|pmid=26542804|last3=Nakdimon|first3=Itay|last4=Ben-Hail|first4=Danya|last5=Mizrachi|first5=Dario|last6=Shoshan-Barmatz|first6=Varda}}</ref>

== 结构 ==
三种VDAC同种型（VDAC1，VDAC2和VDAC3）具有高度保守的DNA序列以及形成宽β-桶结构的3D结构，其中α螺旋N-末端区段驻留以部分闭合通道。<ref>{{Cite journal|title=Charged Residues Distribution Modulates Selectivity of the Open State of Human Isoforms of the Voltage Dependent Anion-Selective Channel|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4146382/|last=Amodeo|first=Giuseppe Federico|last2=Scorciapino|first2=Mariano Andrea|date=2014-08-01|journal=PLoS ONE|issue=8|doi=10.1371/journal.pone.0103879|volume=9|issn=1932-6203|pmc=4146382|pmid=25084457|last3=Messina|first3=Angela|last4=De Pinto|first4=Vito|last5=Ceccarelli|first5=Matteo}}</ref>VDAC1的结构由3个独立的实验室通过X射线晶体学，核磁共振（NMR）光谱学或两者的组合来解决。这些结构研究中的两个用于确定人VDAC1（hVDAC1）结构，而X射线晶体学用于解决鼠VDAC1（mVDAC1）结构，其仅与hVDAC1相差仅两个残基。<ref>{{Cite journal|title=Structure of the human voltage-dependent anion channel|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2557026/|last=Bayrhuber|first=Monika|last2=Meins|first2=Thomas|date=2008-10-07|journal=Proceedings of the National Academy of Sciences of the United States of America|issue=40|doi=10.1073/pnas.0808115105|volume=105|pages=15370–15375|issn=0027-8424|pmc=2557026|pmid=18832158|last3=Habeck|first3=Michael|last4=Becker|first4=Stefan|last5=Giller|first5=Karin|last6=Villinger|first6=Saskia|last7=Vonrhein|first7=Clemens|last8=Griesinger|first8=Christian|last9=Zweckstetter|first9=Markus}}</ref><ref>{{Cite journal|title=Solution structure of the integral human membrane protein VDAC-1 in detergent micelles|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2579273/|last=Hiller|first=Sebastian|last2=Garces|first2=Robert G.|date=2008-08-29|journal=Science (New York, N.Y.)|issue=5893|doi=10.1126/science.1161302|volume=321|pages=1206–1210|issn=0036-8075|pmc=2579273|pmid=18755977|last3=Malia|first3=Thomas J.|last4=Orekhov|first4=Vladislav Y.|last5=Colombini|first5=Marco|last6=Wagner|first6=Gerhard}}</ref><ref name=":4">{{Cite journal|title=The crystal structure of mouse VDAC1 at 2.3 Å resolution reveals mechanistic insights into metabolite gating|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2584669/|last=Ujwal|first=Rachna|last2=Cascio|first2=Duilio|date=2008-11-18|journal=Proceedings of the National Academy of Sciences of the United States of America|issue=46|doi=10.1073/pnas.0809634105|volume=105|pages=17742–17747|issn=0027-8424|pmc=2584669|pmid=18988731|last3=Colletier|first3=Jacques-Philippe|last4=Faham|first4=Salem|last5=Zhang|first5=Jun|last6=Toro|first6=Ligia|last7=Ping|first7=Peipei|last8=Abramson|first8=Jeff}}</ref>这些确定的结构与先前的[[圆二色性|圆二色]]研究一致，该研究预测了[[α螺旋]]和β链结构域的存在。<ref>{{Cite journal|title=Correct Folding of the β-Barrel of the Human Membrane Protein VDAC Requires a Lipid Bilayer|url=http://linkinghub.elsevier.com/retrieve/pii/S0022283607001301|last=Shanmugavadivu|first=Baladhandapani|last2=Apell|first2=Hans-Jürgen|date=2007-04|journal=Journal of Molecular Biology|issue=1|doi=10.1016/j.jmb.2007.01.066|volume=368|pages=66–78|issn=0022-2836|last3=Meins|first3=Thomas|last4=Zeth|first4=Kornelius|last5=Kleinschmidt|first5=Jörg H.|access-date=2018-08-15|archive-date=2021-05-25|archive-url=https://web.archive.org/web/20210525215627/https://linkinghub.elsevier.com/retrieve/pii/S0022283607001301}}</ref>

mVDAC1的结构分析显示由19个两亲性β-链组成的桶状通道，其N-末端和C-末端均朝向线粒体的膜间隙。<ref>{{Cite journal|title=The Role of VDAC in Cell Death: Friend or Foe?|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3288473/|last=McCommis|first=Kyle S.|last2=Baines|first2=Christopher P.|date=2012-6|journal=Biochimica et Biophysica Acta|issue=6|doi=10.1016/j.bbamem.2011.10.025|volume=1818|pages=1444–1450|issn=0006-3002|pmc=3288473|pmid=22062421}}</ref><ref>{{Cite journal|title=The Voltage-Dependent Anion Selective Channel 1 (VDAC1) Topography in the Mitochondrial Outer Membrane as Detected in Intact Cell|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3855671/|last=Tomasello|first=Marianna F.|last2=Guarino|first2=Francesca|date=2013-12-06|journal=PLoS ONE|issue=12|doi=10.1371/journal.pone.0081522|volume=8|issn=1932-6203|pmc=3855671|pmid=24324700|last3=Reina|first3=Simona|last4=Messina|first4=Angela|last5=De Pinto|first5=Vito|access-date=2018-08-15|archive-date=2022-04-02|archive-url=https://web.archive.org/web/20220402100950/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3855671/}}</ref>β-链通过环转连接并以反平行模式排列，除了平行的β-链1和19。<ref name=":4" />通道的高度为40Ẳ，在开口处跨越27Ẳ-20Ẳ的距离，并在打开状态下在N端α-螺旋段处逐渐减小至20Ẳ×14Ẳ。<ref>{{Cite journal|title=Affixing N-terminal α-Helix to the Wall of the Voltage-dependent Anion Channel Does Not Prevent Its Voltage Gating|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3322836/|last=Teijido|first=Oscar|last2=Ujwal|first2=Rachna|date=2012-03-30|journal=The Journal of Biological Chemistry|issue=14|doi=10.1074/jbc.M111.314229|volume=287|pages=11437–11445|issn=0021-9258|pmc=3322836|pmid=22275367|last3=Hillerdal|first3=Carl-Olof|last4=Kullman|first4=Lisen|last5=Rostovtseva|first5=Tatiana K.|last6=Abramson|first6=Jeff}}</ref>闭合状态构象尚未被确定。另外，N-末端具有α螺旋区段，其通过与β-折叠8-18链上的残基的疏水相互作用而保持在通道的内壁。<ref name=":4" />该N-末端可以用作离子移动或蛋白质附着的支架。一个这样的例子被看作是HK1结合的位点。<ref name=":0" />要指出的重要残基是位于氨基酸链上第73个残基的谷氨酸（E73）。该残基存在于VDAC1和VDAC2中，但不存在于VDAC3中。该带电残基的侧链指向磷脂双层，这通常会引起排斥力。然而，E73与VDAC1功能和相互作用有关。<ref>{{Cite journal|title=The role of calcium in VDAC1 oligomerization and mitochondria-mediated apoptosis|url=https://www.ncbi.nlm.nih.gov/pubmed/23542128|last=Keinan|first=Nurit|last2=Pahima|first2=Hadas|date=2013-7|journal=Biochimica Et Biophysica Acta|issue=7|doi=10.1016/j.bbamcr.2013.03.017|volume=1833|pages=1745–1754|issn=0006-3002|pmid=23542128|last3=Ben-Hail|first3=Danya|last4=Shoshan-Barmatz|first4=Varda|access-date=2018-08-15|archive-date=2018-08-21|archive-url=https://web.archive.org/web/20180821124438/https://www.ncbi.nlm.nih.gov/pubmed/23542128}}</ref>

== 功能 ==
VDAC1属于线粒体孔蛋白家族，并且预测与其他VDAC同种型具有相似的生物学功能。<ref>{{Cite journal|title=Identification of the Hypoxia-Inducible Factor 1α-Responsive HGTD-P Gene as a Mediator in the Mitochondrial Apoptotic Pathway|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC387743/|last=Lee|first=Mi-Jung|last2=Kim|first2=Jee-Youn|date=2004-5|journal=Molecular and Cellular Biology|issue=9|doi=10.1128/MCB.24.9.3918-3927.2004|volume=24|pages=3918–3927|issn=0270-7306|pmc=387743|pmid=15082785|last3=Suk|first3=Kyoungho|last4=Park|first4=Jae-Hoon}}</ref>在三种同种型中，VDAC1是主要的钙离子转运通道，并且转录最多。<ref name=":2" /><ref name=":5">{{Cite journal|title=Characterization of human VDAC isoforms: a peculiar function for VDAC3?|url=https://www.ncbi.nlm.nih.gov/pubmed/20138821|last=De Pinto|first=Vito|last2=Guarino|first2=Francesca|date=2010-6|journal=Biochimica Et Biophysica Acta|issue=6-7|doi=10.1016/j.bbabio.2010.01.031|volume=1797|pages=1268–1275|issn=0006-3002|pmid=20138821|last3=Guarnera|first3=Andrea|last4=Messina|first4=Angela|last5=Reina|first5=Simona|last6=Tomasello|first6=Flora M.|last7=Palermo|first7=Vanessa|last8=Mazzoni|first8=Cristina|access-date=2018-08-15|archive-date=2018-08-21|archive-url=https://web.archive.org/web/20180821124444/https://www.ncbi.nlm.nih.gov/pubmed/20138821}}</ref>VDAC1通过在[[线粒体外膜]]（OMM）上运输ATP和其他小代谢物参与细胞代谢，从而允许调节[[三羧酸循环|TCA循环]]，并通过延伸，调节[[活性氧类|活性氧]]（[[ROS]]）的产生。<ref name=":1" />在酵母细胞中，ROS响应于[[氧化应激]]而累积，这导致线粒体功能受损和“小”表型。然而，小型酵母细胞表现出比野生型细胞更长的寿命，并且表明VDAC1在例如衰老类似情况下的保护功能。<ref name=":0" /><ref name=":5" />

== 临床意义 ==
电压依赖性阴离子通道在离子和代谢物转运中都起作用，尽管它们的生理作用是不同的。由于它们的作用，通道的功能障碍可导致各种疾病。 VDAC1通过与[[抗凋亡蛋白家族]]，[[Bcl-2蛋白]]，特别是Bcl-xl和Mcl-1的相互作用而与癌症有关，这些蛋白在癌症过程中过表达。这两种Bcl-2蛋白与VDAC1相互作用以调节穿过OMM的钙离子转运，并最终调节ROS的产生。虽然高水平的ROS诱导细胞死亡，但非致死水平会干扰信号转导通路，从而促进癌细胞的细胞增殖，迁移和侵袭。<ref name=":1" />此外，VDAC1过表达与增加的凋亡反应和抗癌药物和治疗功效相关，进一步支持VDAC1作为癌症治疗的治疗靶标。<ref name=":1" /><ref>{{Cite journal|title=Ca(2+)-mediated regulation of VDAC1 expression levels is associated with cell death induction|url=https://www.ncbi.nlm.nih.gov/pubmed/24704533|last=Weisthal|first=Shira|last2=Keinan|first2=Nurit|date=2014-10|journal=Biochimica Et Biophysica Acta|issue=10|doi=10.1016/j.bbamcr.2014.03.021|volume=1843|pages=2270–2281|issn=0006-3002|pmid=24704533|last3=Ben-Hail|first3=Danya|last4=Arif|first4=Tasleem|last5=Shoshan-Barmatz|first5=Varda|access-date=2018-08-15|archive-date=2018-08-15|archive-url=https://web.archive.org/web/20180815200606/https://www.ncbi.nlm.nih.gov/pubmed/24704533}}</ref>

VDAC1在钙离子转运中的功能也与神经退行性疾病有关。在PD中，VDAC1增加线粒体内的钙离子水平，导致线粒体通透性增加，线粒体膜电位破坏，ROS产生增加，细胞死亡和神经元变性。<ref name=":2" />已显示VDAC1与淀粉样蛋白β（Aβ）相互作用，导致通道的电导增加并最终导致细胞凋亡。<ref name=":3" />

== 参考文献 ==
{{reflist|2}}
{{离子通道|g4}}
[[Category:离子通道]]

VDAC1 - 版本历史

imported>InternetArchiveBot：​补救12个来源，并将0个来源标记为失效。) #IABot (v2.0.8.7

imported>InternetArchiveBot：补救12个来源，并将0个来源标记为失效。) #IABot (v2.0.8.7