生物谷報道:布朗大學(xué)最新研究顯示,，有一種蛋白可能是朊毒病中關(guān)鍵蛋白,，裂解感染性蛋白生成“種子”片段,，然后侵襲腦組織致宿主迅速死亡,。消息振奮人心,，研究者們稱這樣就可以通過藥物干預(yù)控制朊病毒播散,。藥物可阻滯這些蛋白裂解片段過程，從而持久的減慢朊病毒傳播,，包括瘋牛病和綿羊瘋癢病和一些人類罕見疾病克-雅二氏病和庫魯病等疾病的傳播,。由于阿爾茨海默(氏)病和帕金森(氏)等疾病也有相似的蛋白，所以這些藥物亦能減慢這些疾病的進展,。
該項目帶頭人布朗大學(xué)分子生物學(xué)系細胞生物學(xué)家,、生物化學(xué)家Tricia Serio副教授這樣說到，“我們研究發(fā)現(xiàn)這種蛋白裂解片段對朊病毒快速傳播起關(guān)鍵作用，并且對帕金森(氏)病等神經(jīng)退行性病變中毒性蛋白的堆積亦有很大的作用,。”Serio和她研究小組的研究結(jié)果是基于她們2005年《自然》發(fā)表的突破性進展之上的工作,，并在PLoS生物學(xué)網(wǎng)站上發(fā)表?！蹲匀弧冯s志上發(fā)表的研究顯示朊病毒--構(gòu)象先發(fā)生變化,，再進行自我復(fù)制并引起致死性腦病--以超快速度使正常蛋白轉(zhuǎn)變?yōu)楫惓５鞍住＿@種好變壞的構(gòu)象轉(zhuǎn)換就是造成朊病毒大量復(fù)制和傳播的根源,。但科學(xué)家們認(rèn)為傳播過程中還存在另一關(guān)鍵步驟--朊病毒復(fù)合物的裂解片段的存在,。一旦轉(zhuǎn)變成“壞的”或感染性蛋白后，繼續(xù)被裂解成小片段,，就造成了小片段“種子”大量迅速在體內(nèi)倍增,。朊病毒復(fù)制需要有熱休克蛋白(Hsp104)參與，Serio認(rèn)為它可能就具有這種蛋白“粉碎機”的功能,。
為進一步證實,，Serio帶領(lǐng)實驗室組員來研究酵母蛋白質(zhì)Sup35，類似于人類朊病毒PrP蛋白,。她們把Sup35和Hsp104充分混合,，分別觀察活化和失活Hsp104兩種情況，結(jié)果發(fā)現(xiàn)活化組Sup35確實被分解--這是首次證實活體細胞內(nèi)存在這種過程,，Hsp104則是“元兇”,。Serio說到，“怎樣理解蛋白片段加快朊病毒傳播呢,，你可以把它看作蒲公英,，蒲公英頭部就是一簇花朵，而每朵花又含有一粒種子,。當(dāng)風(fēng)吹花落的時候，種子也就隨之播散了,。朊病毒蛋白也同樣,，Hsp104起到風(fēng)的作用，把花瓣扳開并使種子播散”,。Serio還提到,，朊病毒即使不被裂解也存在自身復(fù)制擴增，只不過速度較慢罷了,。因此應(yīng)用阻斷Hsp104活性的藥物只能延緩朊病毒相關(guān)疾病的進展,。
Figure 1.The In Vivo Prion Cycle Is a Multistep Pathway
( 生物谷配圖)
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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).
原文出處:
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
相關(guān)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
作者簡介:
Tricia Serio, Ph.D.
Assistant Professor
Molecular, Cellular Biology Biochemistry
[email protected]
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
