All Title Author
Keywords Abstract

Publish in OALib Journal
ISSN: 2333-9721
APC: Only $99

ViewsDownloads

Relative Articles

More...

以液体核磁共振波谱分析与帕金森氏病相关的I93M突变对人类泛素碳端水解酶结构的影响Hot!

DOI: 10.11938/cjmr20150215, PP. 329-341

Keywords: 帕金森氏病,人类泛素碳端水解酶,蛋白质折叠,液体核磁共振波谱学,化学位移扰动,有序参数,残余偶极耦合

Full-Text   Cite this paper   Add to My Lib

Abstract:

人类泛素碳端水解酶(UCH-L1)是涉及帕金森氏病并且在神经元高度表达的蛋白.UCH-L1的家族性突变与转译后修饰会引起聚集倾向增加与去泛素活性损失,这二者都可能成为致病因素.作者所在实验室之前的研究指出与帕金森氏病相关的突变I93M显著降低UCH-L1的折叠稳定性并且加速其构型展开动力学.该研究使用液体核磁共振分析方法,包括侧链甲基化学位移,松弛骨干动力学和残余偶极耦合,以进一步阐明I93M突变如何影响UCH-L1的结构和动态.结果显示I93M显著影响突变位点周围的疏水核心侧链构型.然而,这样的结构扰动并不会影响在纳秒时间尺度的快速骨干动力学.透过残余偶极耦合分析显示UCH-L1在水溶液中的结构与之前报道的晶体结构有相当显著的偏离,另外I93M突变也导致超出突变位点的远距离结构扰动.这一系列水溶液结构的分析结果可补充之前已知的晶体学数据,并对UCH-L1在帕金森氏病相关的基因突变影响并提供详细的见解.

References

[1]  Thompson R J, Doran J F, Jackson P, et al. PGP 9.5 — a new marker for vertebrate neurons and neuroendocrine cells[J]. Brain Res, 1983, 278: 224-228.
[2]  Day I N. Enolases and PGP9.5 as tissue-specific markers[J]. Biochem Soc Trans, 1992, 20: 637-642.
[3]  Day I N, Thompson R J. UCHL1 (PGP 9.5): neuronal biomarker and ubiquitin system protein[J]. Prog Neurobiol, 2010, 90: 327-362.
[4]  Reyes-Turcu F E, Ventii K H, Wilkinson K D. Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes[J]. Annu Rev Biochem, 2009, 78: 363-397.
[5]  Setsuie R, Wada K. The functions of UCH-L1 and its relation to neurodegenerative diseases[J]. Neurochem Int. 2007, 51: 105-111.
[6]  Fraile J M, Quesada V, Rodriguez D, et al. Deubiquitinases in cancer: new functions and therapeutic options[J]. Oncogene, 2012, 31: 2 373-2 388.
[7]  Snapinn K W, Larson E B, Kawakami H, et al. The UCHL1 S18Y polymorphism and Parkinson's disease in a Japanese population[J]. Parkinsonism Relat Disord, 2011, 17: 473-475.
[8]  Ardley H C, Scott G B, Rose S A, et al. UCH-L1 aggresome formation in response to proteasome impairment indicates a role in inclusion formation in Parkinson's disease[J]. J Neurochem, 2004, 90: 379-391.
[9]  Leroy E, Boyer R, Auburger G, et al. Polymeropoulos, The ubiquitin pathway in Parkinson's disease[J]. Nature, 1998, 395: 451-452.
[10]  Kabuta T, Furuta A, Aoki S, et al. Aberrant interaction between Parkinson disease-associated mutant UCH-L1 and the lysosomal receptor for chaperone-mediated autophagy[J]. J Biol Chem, 2008, 283: 23 731-23 738.
[11]  Kabuta T, Setsuie R, Mitsui T, et al. Aberrant molecular properties shared by familial Parkinson's disease-associated mutant UCH-L1 and carbonyl-modified UCH-L1[J]. Hum Mol Genet, 2008, 17: 1 482-1 496.
[12]  Das C, Hoang Q Q, Kreinbring C A, et al. Structural basis for conformational plasticity of the Parkinson's disease-associated ubiquitin hydrolase UCH-L1[J]. Proc Natl Acad Sci USA, 2006, 103: 4 675-4 680.
[13]  Boudreaux D A, Maiti T K, Davies C W, et al. Ubiquitin vinyl methyl ester binding orients the misaligned active site of the ubiquitin hydrolase UCHL1 into productive conformation[J]. Proc Natl Acad Sci USA, 2010, 107: 9 117-9 122.
[14]  Case A, Stein R L. Mechanistic studies of ubiquitin C-terminal hydrolase L1[J]. Biochemistry, 2006, 45: 2 443-2 452.
[15]  Andersson F I, Werrell E F, McMorran L, et al. The effect of Parkinson's-disease-associated mutations on the deubiquitinating enzyme UCH-L1[J]. J Mol Biol, 2011, 407: 261-272.
[16]  Andersson F I, Jackson S E, Hsu S T. Backbone assignments of the 26 kDa neuron-specific ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1)[J]. Biomol NMR Assign, 2010, 4: 41-43.
[17]  Cavangh J, Skelton N J, Fairbrother W J, et al. Palmer III, Protein NMR spectroscopy: principles and practice (2nd ed)[M]. Elsevier, 2006.
[18]  Hsu S T D, Behrens C, Cabrita L D, et al. 1H, 15N and 13C assignments of yellow fluorescent protein (YFP) Venus[J]. Biomol NMR Assign, 2009, 3: 67-72.
[19]  Hsu S T D, Cabrita L D, Fucini P, et al. Structure, dynamics and folding of an immunoglobulin domain of the gelation factor (ABP-120) from Dictyostelium discoideum[J]. J Mol Biol, 2009, 388: 865-879.
[20]  Goddard T D, Kneller D G. Sparky Version 3.115[M]. San Francisco: University of California, 2008.
[21]  Dosset P, Hus J C, Blackledge M, et al. Efficient analysis of macromolecular rotational diffusion from heteronuclear relaxation data[J]. J Biomol NMR, 2000, 16: 23-28.
[22]  Zweckstetter M, Bax A. Characterization of molecular alignment in aqueous suspensions of Pf1 bacteriophage[J]. J Biomol NMR, 2001, 20: 365-377.
[23]  Zweckstetter M. NMR: prediction of molecular alignment from structure using the PALES software[J]. Nat Protoc, 2008, 3: 679-690.
[24]  Farrow N A, Muhandiram R, Singer A U, et al. Backbone dynamics of a free and phosphopeptide-complexed Src homology 2 domain studied by 15N NMR relaxation[J]. Biochemistry, 1994, 33: 5 984-6 003.
[25]  Werrell E F. Biophysical Studies on the Neuronal Ubiquitin C-terminal hydrolase, UCH-L1, Ph.D. thesis[M]. Cambridge: University of Cambridge, 2011.
[26]  Koharudin L M, Liu H, Di Maio R, et al. Cyclopentenone prostaglandin-induced unfolding and aggregation of the Parkinson disease-associated UCH-L1[J]. Proc Natl Acad Sci USA, 2010, 107: 6 835-6 840.
[27]  Liu Y, Lashuel H A, Choi S, et al. Discovery of inhibitors that elucidate the role of UCH-L1 activity in the H1299 lung cancer cell line[J]. Chem Biol, 2003, 10: 837-846.
[28]  Mitsui T, Hirayama K, Aoki S, et al. Identification of a novel chemical potentiator and inhibitors of UCH-L1 by in silico drug screening[J]. Neurochem Int, 2010, 56: 679-686.
[29]  Tse H S, Hu H Y, Sze K H. Backbone and side-chain 1H, 15N and 13C resonance assignments of S18Y mutant of ubiquitin carboxy-terminal hydrolase L1[J]. Biomol NMR Assign, 2011, 5: 165-168.
[30]  Kabuta T, Wada K. Insights into links between familial and sporadic Parkinson's disease: physical relationship between UCH-L1 variants and chaperone-mediated autophagy[J]. Autophagy, 2008, 4: 827-829.
[31]  Koseki Y, Kinjo T, Kuroki M, et al. Aberrant structures of Parkinson′s disease-associated ubiquitin C-terminal hydrolase L1 predicted by molecular dynamics[J]. Chem Phy Lett, 2012, 535: 163-168.
[32]  Grishaev A, Tugarinov V, Kay L E, et al. Refined solution structure of the 82 kDa enzyme malate synthase G from joint NMR and synchrotron SAXS restraints[J]. J Biomol NMR, 2008, 40: 95-106.

Full-Text

Contact Us

service@oalib.com

QQ:3279437679

WhatsApp +8615387084133