SWI/SNF

現有可用的蛋白結構：
Pfam	結構（旧版） / ECOD
PDB	RCSB PDB; PDBe; PDBj
PDBsum（英语：PDBsum）	結構概要

SWIB
SWIB
	拟南芥假定蛋白AT5G14170的SWIB/MDM2结构域的解析结构
鑑定
標誌	SWIB
Pfam	PF02201（旧版）
InterPro（英语：InterPro）	IPR003121
SMART（英语：Simple Modular Architecture Research Tool）	SWIB
SCOP（英语：Structural Classification of Proteins）	1ycr / SUPFAM
Pfam
現有可用的蛋白結構：
Pfam	結構（旧版） / ECOD
PDB	RCSB PDB; PDBe; PDBj
PDBsum（英语：PDBsum）	結構概要

在分子生物学领域，SWI/SNF（英語：SWItch/Sucrose NonFermentable）^[1]^[2]是同时存在于真核生物及原核生物中的一种核小体重塑复合物。简而言之，它们是一群与重塑DNA包装方式有关的蛋白质。SWI/SNF由多种蛋白构成，这些蛋白往往是SWI及SNF基因（SWI1、SWI2/SNF2、SWI3、SWI5、SWI6）的产物以及一些其它多肽^[3]。SWI/SNF受DNA刺激后表现出ATP酶活性，利用ATP破坏并重塑核小体的组蛋白和DNA之间相互作用的稳定性，不过这种结构改变的精确性质仍未明确。

人体中与SWI/SNF相似的蛋白是BAF（与SWI/SNF-A相似）和PBAF（与SWI/SNF-B相似）。BAF表示“BRG1（英语：SMARCA4）或HRBM（英语：SMARCA2）相关因子”，PBAF则表示“聚溴相关的BAF”^[4]。

作用机理

人们发现酵母中的SWI/SNF复合物能使DNA在不同的位置与组蛋白结合成核小体^[5]。目前已提出两种SWI/SNF重塑核小体的机制^[6]。一种机制叫做“扭转扩散”，认为核小体DNA中的扭转缺陷发生单向扩散，使DNA从进入核小体的地方开始贴着组蛋白八聚体的表面螺旋状地传播。另一种机制叫做“突起”或“环再捕获”，意即DNA在核小体边缘与之分离，形成一环状突起。环状突起在组蛋白八聚体表面像波浪般传播，最后在核小体内部重新与之结合。这样DNA就在和组蛋白接触点数量不变的情况下完成位移^[7]。最新研究提出了与“扭转扩散”机制相抵触的有力证据，使“环再捕获”模型更有说服力^[8]。

肿瘤抑制作用

人类的SWI/SNF复合物（mSWI/SNF）对很多人类恶性肿瘤有抑制作用。1998年首先发现它能抑制横纹肌样瘤（一种罕见的儿童恶性肿瘤）^[9]。随着DNA测序成本逐渐降低，2010年左右许多肿瘤首次得到测序。其中数项研究表明SWI/SNF对多种恶性肿瘤有抑制作用^[10]^[11]^[12]^[13]。对多个测序研究结果的荟萃分析表明，大约20%的人类恶性肿瘤中SWI/SNF存在变异^[14]。

SWIB/MDM2蛋白结构域

SWIB/MDM2蛋白结构域，全称是SWI/SNF复合物B/MDM2（英语：MDM2）蛋白结构域是相当重要的蛋白结构域。这个蛋白结构域在SWI/SNF复合物B和p53肿瘤抑制蛋白的负向调节蛋白MDM2中均存在。已证明MDM2与SWIB复合物同源^[15]。

功能

SWIB/MDM2蛋白结构域的主要功能是协助基因表达。在酵母中，它表达BADH2（英语：betaine-aldehyde dehydrogenase）、GAL1、GAL4和SUC2等数个基因。该蛋白结构域作用是促进基因转录。它有ATP酶的活性，能分解细胞基本能量“货币”单位ATP，放出能量以破坏DNA和组蛋白结合的稳定性，从而干扰染色质，并开放可供转录因子结合的位点，这就促进了基因的转录^[16]。

系列成员

以下列出酵母SWI/SNF系列基因成员以及人类相应的直系同源基因^[17]：

酵母	人类	功能
SWI1	ARID1A（英语：ARID1A）、ARID1B（英语：ARID1B）	含有LXXLL核受体结合基序
SWI2/SNF2	SMARCA4（英语：SMARCA4）	ATP依赖的染色质重塑
SWI3	SMARCC1（英语：SMARCC1）、SMARCC2（英语：SMARCC2）	功能未知的相似序列
SWP73	SMARCD1（英语：SMARCD1）、SMARCD2（英语：SMARCD2）、SMARCD3（英语：SMARCD3）	功能未知的相似序列
SWP61	ACTL6A（英语：ACTL6A）、ACTL6B（英语：ACTL6B）	肌动蛋白样蛋白

历史

SWI/SNF首先发现于釀酒酵母（Saccharomyces cerevisiae）中，以交替（switching，缩写SWI）型和不发酵蔗糖型（sucrose nonfermenting，缩写SNF）型交配后所得的酵母命名^[16]。

另见

MDM2（英语：MDM2）
染色质结构重塑复合物（英语：Chromatin Structure Remodeling (RSC) Complex）
转录共调控物（英语：Transcription coregulator）

参考文献 s

^ Neigeborn L, Carlson M. Genes Affecting the Regulation of SUC2 Gene Expression by Glucose Repression in SACCHAROMYCES CEREVISIAE. Genetics. 1984, 108 (4): 845–58 [2014-01-06]. PMC 1224269 . PMID 6392017. （原始内容存档于2008-08-21）.
^ Stern M, Jensen R, Herskowitz I. Five SWI genes are required for expression of the HO gene in yeast. J. Mol. Biol. 1984, 178 (4): 853–68. PMID 6436497. doi:10.1016/0022-2836(84)90315-2.
^ Pazin MJ, Kadonaga JT. SWI2/SNF2 and related proteins: ATP-driven motors that disrupt protein-DNA interactions?. Cell. 1997, 88 (6): 737–40. PMID 9118215. doi:10.1016/S0092-8674(00)81918-2.
^ Nie Z, Yan Z, Chen EH, Sechi S, Ling C, Zhou S, Xue Y, Yang D, Murray D, Kanakubo E, Cleary ML, Wang W. Novel SWI/SNF chromatin-remodeling complexes contain a mixed-lineage leukemia chromosomal translocation partner. Mol. Cell. Biol. April 2003, 23 (8): 2942–52. PMC 152562 . PMID 12665591. doi:10.1128/MCB.23.8.2942-2952.2003.
^ Whitehouse I, Flaus A, Cairns BR, White MF, Workman JL, Owen-Hughes T. Nucleosome mobilization catalysed by the yeast SWI/SNF complex. Nature. August 1999, 400 (6746): 784–7. PMID 10466730. doi:10.1038/23506.
^ van Holde K, Yager T. Models for chromatin remodeling: a critical comparison. Biochem. Cell Biol. 2003, 81 (3): 169–72. PMID 12897850. doi:10.1139/o03-038.
^ Flaus A, Owen-Hughes T. Mechanisms for nucleosome mobilization. Biopolymers. 2003, 68 (4): 563–78. PMID 12666181. doi:10.1002/bip.10323.
^ Zofall M, Persinger J, Kassabov SR, Bartholomew B. Chromatin remodeling by ISW2 and SWI/SNF requires DNA translocation inside the nucleosome. Nat. Struct. Mol. Biol. 2006, 13 (4): 339–46. PMID 16518397. doi:10.1038/nsmb1071.
^ Versteege I, Sévenet N, Lange J, Rousseau-Merck MF, Ambros P, Handgretinger R, Aurias A, Delattre O. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature. July 1998, 394 (6689): 203–6. PMID 9671307. doi:10.1038/28212.
^ Wiegand KC, Shah SP, Al-Agha OM, Zhao Y, Tse K, Zeng T, Senz J, McConechy MK, Anglesio MS, Kalloger SE, Yang W, Heravi-Moussavi A, Giuliany R, Chow C, Fee J, Zayed A, Prentice L, Melnyk N, Turashvili G, Delaney AD, Madore J, Yip S, McPherson AW, Ha G, Bell L, Fereday S, Tam A, Galletta L, Tonin PN, Provencher D, Miller D, Jones SJ, Moore RA, Morin GB, Oloumi A, Boyd N, Aparicio SA, Shih IeM, Mes-Masson AM, Bowtell DD, Hirst M, Gilks B, Marra MA, Huntsman DG. ARID1A mutations in endometriosis-associated ovarian carcinomas. N. Engl. J. Med. October 2010, 363 (16): 1532–43. PMC 2976679 . PMID 20942669. doi:10.1056/NEJMoa1008433.
^ Li M, Zhao H, Zhang X, Wood LD, Anders RA, Choti MA, Pawlik TM, Daniel HD, Kannangai R, Offerhaus GJ, Velculescu VE, Wang L, Zhou S, Vogelstein B, Hruban RH, Papadopoulos N, Cai J, Torbenson MS, Kinzler KW. Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nat. Genet. September 2011, 43 (9): 828–9. PMC 3163746 . PMID 21822264. doi:10.1038/ng.903.
^ Shain AH, Giacomini CP, Matsukuma K, Karikari CA, Bashyam MD, Hidalgo M, Maitra A, Pollack JR. Convergent structural alterations define SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeler as a central tumor suppressive complex in pancreatic cancer. Proc. Natl. Acad. Sci. U.S.A. January 2012, 109 (5): E252–9. PMC 3277150 . PMID 22233809. doi:10.1073/pnas.1114817109.
^ Varela I, Tarpey P, Raine K, Huang D, Ong CK, Stephens P, Davies H, Jones D, Lin ML, Teague J, Bignell G, Butler A, Cho J, Dalgliesh GL, Galappaththige D, Greenman C, Hardy C, Jia M, Latimer C, Lau KW, Marshall J, McLaren S, Menzies A, Mudie L, Stebbings L, Largaespada DA, Wessels LF, Richard S, Kahnoski RJ, Anema J, Tuveson DA, Perez-Mancera PA, Mustonen V, Fischer A, Adams DJ, Rust A, Chan-on W, Subimerb C, Dykema K, Furge K, Campbell PJ, Teh BT, Stratton MR, Futreal PA. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature. January 2011, 469 (7331): 539–42. PMC 3030920 . PMID 21248752. doi:10.1038/nature09639.
^ Shain AH, Pollack JR. The spectrum of SWI/SNF mutations, ubiquitous in human cancers. PLoS ONE. 2013, 8 (1): e55119. PMC 3552954 . PMID 23355908. doi:10.1371/journal.pone.0055119.
^ Bennett-Lovsey R, Hart SE, Shirai H, Mizuguchi K. The SWIB and the MDM2 domains are homologous and share a common fold.. Bioinformatics. 2002, 18 (4): 626–30. PMID 12016060. doi:10.1093/bioinformatics/18.4.626.
^ ^16.0 ^16.1 Decristofaro MF, Betz BL, Rorie CJ, Reisman DN, Wang W, Weissman BE. Characterization of SWI/SNF protein expression in human breast cancer cell lines and other malignancies.. J Cell Physiol. 2001, 186 (1): 136–45. PMID 11147808. doi:10.1002/1097-4652(200101)186:1<136::AID-JCP1010>3.0.CO;2-4.
^ Collingwood TN, Urnov FD, Wolffe AP. Nuclear receptors: coactivators, corepressors and chromatin remodeling in the control of transcription. J. Mol. Endocrinol. 1999, 23 (3): 255–75. PMID 10601972. doi:10.1677/jme.0.0230255.

外部链接

Nextbio^{[失效連結]}

[pmid6392017-1] Neigeborn L, Carlson M. Genes Affecting the Regulation of SUC2 Gene Expression by Glucose Repression in SACCHAROMYCES CEREVISIAE. Genetics. 1984, 108 (4): 845–58 [2014-01-06]. PMC 1224269 . PMID 6392017. （原始内容存档于2008-08-21）.

[pmid6436497-2] Stern M, Jensen R, Herskowitz I. Five SWI genes are required for expression of the HO gene in yeast. J. Mol. Biol. 1984, 178 (4): 853–68. PMID 6436497. doi:10.1016/0022-2836(84)90315-2.

[pmid9118215-3] Pazin MJ, Kadonaga JT. SWI2/SNF2 and related proteins: ATP-driven motors that disrupt protein-DNA interactions?. Cell. 1997, 88 (6): 737–40. PMID 9118215. doi:10.1016/S0092-8674(00)81918-2.

[pmid12665591-4] Nie Z, Yan Z, Chen EH, Sechi S, Ling C, Zhou S, Xue Y, Yang D, Murray D, Kanakubo E, Cleary ML, Wang W. Novel SWI/SNF chromatin-remodeling complexes contain a mixed-lineage leukemia chromosomal translocation partner. Mol. Cell. Biol. April 2003, 23 (8): 2942–52. PMC 152562 . PMID 12665591. doi:10.1128/MCB.23.8.2942-2952.2003.

[pmid10466730-5] Whitehouse I, Flaus A, Cairns BR, White MF, Workman JL, Owen-Hughes T. Nucleosome mobilization catalysed by the yeast SWI/SNF complex. Nature. August 1999, 400 (6746): 784–7. PMID 10466730. doi:10.1038/23506.

[pmid12897850-6] van Holde K, Yager T. Models for chromatin remodeling: a critical comparison. Biochem. Cell Biol. 2003, 81 (3): 169–72. PMID 12897850. doi:10.1139/o03-038.

[pmid12666181-7] Flaus A, Owen-Hughes T. Mechanisms for nucleosome mobilization. Biopolymers. 2003, 68 (4): 563–78. PMID 12666181. doi:10.1002/bip.10323.

[pmid16518397-8] Zofall M, Persinger J, Kassabov SR, Bartholomew B. Chromatin remodeling by ISW2 and SWI/SNF requires DNA translocation inside the nucleosome. Nat. Struct. Mol. Biol. 2006, 13 (4): 339–46. PMID 16518397. doi:10.1038/nsmb1071.

[pmid9671307-9] Versteege I, Sévenet N, Lange J, Rousseau-Merck MF, Ambros P, Handgretinger R, Aurias A, Delattre O. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature. July 1998, 394 (6689): 203–6. PMID 9671307. doi:10.1038/28212.

[pmid20942669-10] Wiegand KC, Shah SP, Al-Agha OM, Zhao Y, Tse K, Zeng T, Senz J, McConechy MK, Anglesio MS, Kalloger SE, Yang W, Heravi-Moussavi A, Giuliany R, Chow C, Fee J, Zayed A, Prentice L, Melnyk N, Turashvili G, Delaney AD, Madore J, Yip S, McPherson AW, Ha G, Bell L, Fereday S, Tam A, Galletta L, Tonin PN, Provencher D, Miller D, Jones SJ, Moore RA, Morin GB, Oloumi A, Boyd N, Aparicio SA, Shih IeM, Mes-Masson AM, Bowtell DD, Hirst M, Gilks B, Marra MA, Huntsman DG. ARID1A mutations in endometriosis-associated ovarian carcinomas. N. Engl. J. Med. October 2010, 363 (16): 1532–43. PMC 2976679 . PMID 20942669. doi:10.1056/NEJMoa1008433.

[pmid21822264-11] Li M, Zhao H, Zhang X, Wood LD, Anders RA, Choti MA, Pawlik TM, Daniel HD, Kannangai R, Offerhaus GJ, Velculescu VE, Wang L, Zhou S, Vogelstein B, Hruban RH, Papadopoulos N, Cai J, Torbenson MS, Kinzler KW. Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nat. Genet. September 2011, 43 (9): 828–9. PMC 3163746 . PMID 21822264. doi:10.1038/ng.903.

[pmid22233809-12] Shain AH, Giacomini CP, Matsukuma K, Karikari CA, Bashyam MD, Hidalgo M, Maitra A, Pollack JR. Convergent structural alterations define SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeler as a central tumor suppressive complex in pancreatic cancer. Proc. Natl. Acad. Sci. U.S.A. January 2012, 109 (5): E252–9. PMC 3277150 . PMID 22233809. doi:10.1073/pnas.1114817109.

[pmid21248752-13] Varela I, Tarpey P, Raine K, Huang D, Ong CK, Stephens P, Davies H, Jones D, Lin ML, Teague J, Bignell G, Butler A, Cho J, Dalgliesh GL, Galappaththige D, Greenman C, Hardy C, Jia M, Latimer C, Lau KW, Marshall J, McLaren S, Menzies A, Mudie L, Stebbings L, Largaespada DA, Wessels LF, Richard S, Kahnoski RJ, Anema J, Tuveson DA, Perez-Mancera PA, Mustonen V, Fischer A, Adams DJ, Rust A, Chan-on W, Subimerb C, Dykema K, Furge K, Campbell PJ, Teh BT, Stratton MR, Futreal PA. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature. January 2011, 469 (7331): 539–42. PMC 3030920 . PMID 21248752. doi:10.1038/nature09639.

[pmid23355908-14] Shain AH, Pollack JR. The spectrum of SWI/SNF mutations, ubiquitous in human cancers. PLoS ONE. 2013, 8 (1): e55119. PMC 3552954 . PMID 23355908. doi:10.1371/journal.pone.0055119.

[pmid12016060-15] Bennett-Lovsey R, Hart SE, Shirai H, Mizuguchi K. The SWIB and the MDM2 domains are homologous and share a common fold.. Bioinformatics. 2002, 18 (4): 626–30. PMID 12016060. doi:10.1093/bioinformatics/18.4.626.

[pmid11147808-16] 16.0 ^16.1 Decristofaro MF, Betz BL, Rorie CJ, Reisman DN, Wang W, Weissman BE. Characterization of SWI/SNF protein expression in human breast cancer cell lines and other malignancies.. J Cell Physiol. 2001, 186 (1): 136–45. PMID 11147808. doi:10.1002/1097-4652(200101)186:1<136::AID-JCP1010>3.0.CO;2-4.

[pmid10601972-17] Collingwood TN, Urnov FD, Wolffe AP. Nuclear receptors: coactivators, corepressors and chromatin remodeling in the control of transcription. J. Mol. Endocrinol. 1999, 23 (3): 255–75. PMID 10601972. doi:10.1677/jme.0.0230255.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]