生物谷报道:布朗大学最新研究显示，有一种蛋白可能是朊毒病中关键蛋白，裂解感染性蛋白生成“种子”片段，然后侵袭脑组织致宿主迅速死亡。消息振奋人心，研究者们称这样就可以通过药物干预控制朊病毒播散。药物可阻滞这些蛋白裂解片段过程，从而持久的减慢朊病毒传播，包括疯牛病和绵羊疯痒病和一些人类罕见疾病克-雅二氏病和库鲁病等疾病的传播。由于阿尔茨海默(氏)病和帕金森(氏)等疾病也有相似的蛋白，所以这些药物亦能减慢这些疾病的进展。
该项目带头人布朗大学分子生物学系细胞生物学家、生物化学家Tricia Serio副教授这样说到，“我们研究发现这种蛋白裂解片段对朊病毒快速传播起关键作用，并且对帕金森(氏)病等神经退行性病变中毒性蛋白的堆积亦有很大的作用。”Serio和她研究小组的研究结果是基于她们2005年《自然》发表的突破性进展之上的工作，并在PLoS生物学网站上发表。《自然》杂志上发表的研究显示朊病毒--构象先发生变化，再进行自我复制并引起致死性脑病--以超快速度使正常蛋白转变为异常蛋白。这种好变坏的构象转换就是造成朊病毒大量复制和传播的根源。但科学家们认为传播过程中还存在另一关键步骤--朊病毒复合物的裂解片段的存在。一旦转变成“坏的”或感染性蛋白后，继续被裂解成小片段，就造成了小片段“种子”大量迅速在体内倍增。朊病毒复制需要有热休克蛋白(Hsp104)参与，Serio认为它可能就具有这种蛋白“粉碎机”的功能。
为进一步证实，Serio带领实验室组员来研究酵母蛋白质Sup35，类似于人类朊病毒PrP蛋白。她们把Sup35和Hsp104充分混合，分别观察活化和失活Hsp104两种情况，结果发现活化组Sup35确实被分解--这是首次证实活体细胞内存在这种过程，Hsp104则是“元凶”。Serio说到，“怎样理解蛋白片段加快朊病毒传播呢，你可以把它看作蒲公英，蒲公英头部就是一簇花朵，而每朵花又含有一粒种子。当风吹花落的时候，种子也就随之播散了。朊病毒蛋白也同样，Hsp104起到风的作用，把花瓣扳开并使种子播散”。Serio还提到，朊病毒即使不被裂解也存在自身复制扩增，只不过速度较慢罢了。因此应用阻断Hsp104活性的药物只能延缓朊病毒相关疾病的进展。
Figure 1.The In Vivo Prion Cycle Is a Multistep Pathway
( 生物谷配图)
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Existing prion complexes (black ball and loop) replicate by stimulating the conversion of either newly synthesized or non-prion conformer of the protein (gray ball and stick) to the prion form (black and gray ball and loop, step 1). Prion complexes must be stably maintained (step 2), but continually divided to generate new prion templates for additional rounds of protein-state replication (step 3). The smaller complexes generated by this division are efficiently transmitted to daughter cells (step 4).
原文出处:
Published January 23, 2007 - RESEARCH ARTICLE
Hsp104-Dependent Remodeling of Prion Complexes Mediates Protein-Only Inheritance Satpute-Krishnan P, Langseth SX, Serio TR PLoS Biology Vol. 5, No. 2, e24 doi:10.1371/journal.pbio.0050024
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Citation
相关基因:
PRNP
Official Symbol: PRNP and Name: prion protein (p27-30) (Creutzfeldt-Jakob disease, Gerstmann-Strausler-Scheinker syndrome, fatal familial insomnia) [Homo sapiens]
Other Aliases: ASCR, CD230, CJD, GSS, MGC26679, PRIP, PrP, PrP27-30, PrP33-35C, PrPc
Other Designations: CD230 antigen; major prion protein; prion protein; prion protein PrP; prion-related protein
Chromosome: 20; Location: 20p13
MIM: 176640
GeneID: 5621
作者简介:
Tricia Serio, Ph.D.
Assistant Professor
Molecular, Cellular Biology Biochemistry
Tricia_Serio@Brown.EDU
Brief Bio
Professor Serio received her B.S. in Molecular Biology from Lehigh University in 1991 and completed her graduate work in Molecular Biochemistry and Biophysics as a fellow of the Howard Hughes Medical Institute at Yale University (M.Phil 1995, Ph.D. 1997). From 1997 through 2002, she was a post-doctoral fellow of the Damon Runyon-Walter Winchell Cancer Research Fund at the University of Chicago and a recipient of the Howard Temin Award from the National Cancer Institute at Yale University. She joined the faculty at Brown University as an assistant professor in 2002 and is a Pew Scholar in the Biomedical Sciences. Her research focuses on self-perpetuating protein conformations in the yeast Saccharomyces cerevisiae as model for severe neurodegenerative diseases in mammals.
Overview
In a variety of systems, proteins have been linked to processes historically limited to nucleic acids, such as infectivity and inheritance. Such proteins, termed prions, adopt multiple physical and therefore functional states in vivo, an attribute underlying their atypical roles in the cell. Our work seeks to elucidate the molecular mechanisms that module prion protein conformational flexibility in vivo using the yeast Saccharomyces cerevisiae as an experimental model.
On the Web
Serio Lab
Tricia Serio one of 2003 Pew Scholars
Prions Rapidly "Remodel" Good Protein Into Bad
Research Description/Clinical Interests
A protein's activity is a direct manifestation of its structure, and the cell expends considerable energy to ensure that a nascent protein efficiently adopts a single, correct three-dimensional fold. In theory, the road map from synthesis to functional form is specified by the protein's primary sequence of amino acids, but in practice, nascent proteins frequently misfold into alternate conformations. In most instances, cells recognize these aberrant forms and target them to molecular chaperones for refolding or to proteases for destruction. However, a group of proteins known as prions is an exception to these rules. Prions have the capacity to adopt multiple stable forms in vivo, and, since a protein's structure determines its function, cells containing the same protein in two different conformations will have different phenotypes. For instance, one conformation of the mammalian prion protein PrP is non-pathogenic, while other forms likely mediate the development of severe neurodegenerative disease (e.g., mad cow disease, Creutzfeldt-Jacob Disease, kuru). Remarkably, some of these diseases are infectious, suggesting that the aberrant protein conformations are acting as genetic elements, a role historically limited to nucleic acids.
How do prion proteins act in these atypical roles? A fine-tuned regulation of prion protein structural flexibility is key. If each newly synthesized molecule of a prion protein could independently choose between forms, all cells would display a single phenotype that is the average of the two states. The appearance of distinct phenotypes in vivo suggests that while the prion protein remains flexible enough to access multiple forms, its folding is somehow constrained in any given cell such that only one form persists.
Our current work seeks to elucidate the molecular mechanisms underlying the near-faithful propagation of prion forms in vivo using the Sup35/[PSI+] prion of Saccharomyces cerevisiae as an experimental model.
Curriculum Vitae
Download Tricia Serio's Curriculum Vitae in PDF Format
Honors and Awards
Howard Temin Award
Pew Scholar in the Biomedical Sciences
Funded Research
Modulation of Translation Termination Fidelity
National Cancer Institute (K01 CA96402-05)
9/01/2001-8/31/2006
Principal Investigator: Tricia Serio
Prion Regulation of Translation Termination
Pew Scholars Program in the Biomedical Sciences (2001-000389)
7/01/2003 - 6/30/2007
Principal Investigator: Tricia Serio
Prion Cycle Regulation In Vivo
NIH/NIGMS (R01 GM069802-01)
2/01/2006 – 1/31/2011
Principal Investigator: Tricia Serio
Courses Taught
Advanced Biochemistry (BI0127)
Foundations for Advanced Study in Experimental Biology (BIO203)
Publications
Satpute-Krishnan P and Serio T.R. Prion Protein Remodelling Confers An Immediate Phenotypic Switch. Nature 437: 262-5 (2005).
Serio T.R. and Lindquist S.L. The Yeast Prion [PSI+]:Molecular Insights and Functional Consequences. Adv Protein Chem 59:391-412 (2001) .
Serio T.R. and Lindquist S.L. [PSI+], Sup35 and Chaperones. Adv Protein Chem 57:335-66 (2001).
Serio T.R., Cashikar A.G., Kowal A.S., Sawicki, G., and Lindquist S.L. Self-Perpetuating Changes in Sup35 Protein Conformation as a Mechanism of Heredity in yeast. i
