Mechanisms of Polytopic Protein Biogenesis in the ER
Mechanisms of Polytopic Protein Biogenesis in the ER
批准号:
6751215
负责人:
WILLIAM R SKACH
金额:
$25.91万
依托单位国家:
美国
项目类别:
财政年份:
1996
资助国家:
美国
项目状态:
已结题
起止时间:
1996-08-01 至 2005-08-31
关键词:
HeLa cellsXenopus oocyteanimal tissuecell free systemchimeric proteinscrosslinkendoplasmic reticulumlaboratory rabbitmembrane biogenesismembrane proteinsmicroinjectionsmolecular assembly /self assemblymolecular chaperonesprotein biosynthesisprotein engineeringprotein foldingprotein isoformsprotein structure functionprotein transporttissue /cell culturewater channel
中文摘要
描述(改编自申请人摘要):该项目的长期目标
英文摘要
DESCRIPTION (Adapted from the Applicant's Abstract): The long term goal of this
proposal is to establish the molecular basis by which eukaryotic polytopic
membrane proteins integrate, fold and assemble in the lipid bilayer of the
endoplasmic reticulum (ER). Aquaporins represent a prototype class of polytopic
proteins that contain six transmembrane (TM) segments and form selective
water-permeable channels in cell membranes. At least six aquaporins are
expressed in the mammalian kidney where they play critical roles in fluId and
electrolyte homeostasis. While the basic steps of aquaporin assembly in ER have
recently been described, very little is known about how cellular machinery
mediates specific translocation, membrane integration, and folding events
required to establish AQP topology. This is a major limitation in our
understanding of normal renal physiology and in particular, pathologic states
where aquaporin folding is disrupted, e.g. nephrogenic diabetes insipidus.
Recent studies from our laboratory, now provide for the first time, a means to
define the molecular interactions responsible for different and novel polytopic
protein folding pathways. Because of their significant role in normal
physiology, their relatively simple architecture, and their unusual biogenesis
mechanisms, aquaporins represent ideal candidates for such a study.
The specific aims are: i) to characterize different molecular pathways of
aquaporm assembly in the ER membrane, ii) to define how primary structural
determinants generate variations in these folding pathways, and iii) to
identify novel components within the ER that are required for specialized
aspects of aquaporin biogenesis. Proposed experiments will use cell free
translation systems to incorporate photoactive crosslinking probes at
engineered sites in native, mutant and chimeric aquaporin proteins. These
experiments will define molecular interactions between the nascent polypeptide
and ER translocation machinery that mediate protein folding and determine how
subtle variations in sequence influence normal biogenesis events and topologic
outcome. Finally novel factors required for aquaporin maturation will be
identified by fractionation and heterologous reconstitution of translocation
competent ER membranes that exhibit distinct differences in aquaponn
maturation. Together these studies will provide a major advance in our
knowledge of the molecular events involved in polytopic protein biogenesis and
will establish a foundation for understanding how inherited mutations disrupt
biogenesis in human disease.
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会议论文
Biogenesis and Molecular Pathogenesis of CFTR
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批准号:7992505
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项目类别:
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资助金额:$9.83万
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财政年份:2010
-
负责人:WILLIAM R SKACH
-
依托单位:
BIOGENESIS AND MOLECULAR PATHOGENESIS OF CFTR
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批准号:2874278
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项目类别:
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资助金额:$21.65万
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财政年份:1996
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负责人:WILLIAM R SKACH
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依托单位:
Mechanisms of Polytopic Protein Biogenesis in the ER
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批准号:6985675
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项目类别:
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资助金额:$29.93万
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财政年份:1996
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负责人:WILLIAM R SKACH
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依托单位:
Biogenesis and Molecular Pathogenesis of CFTR
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批准号:8039896
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项目类别:
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资助金额:$30.19万
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财政年份:1996
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负责人:WILLIAM R SKACH
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依托单位:
Mechanisms of Polytopic Protein Biogenesis in the ER
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批准号:6636152
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项目类别:
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资助金额:$25.97万
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财政年份:1996
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负责人:WILLIAM R SKACH
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依托单位:
Mechanisms of Polytopic Protein Biogenesis in the ER
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批准号:6331896
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项目类别:
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资助金额:$24.72万
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财政年份:1996
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负责人:WILLIAM R SKACH
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依托单位:
Biogenesis and Molecular Pathogenesis of CFTR
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批准号:7781290
-
项目类别:
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资助金额:$30.49万
-
财政年份:1996
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负责人:WILLIAM R SKACH
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依托单位:
Biogenesis and Molecular Pathogenesis of CFTR
-
批准号:8246410
-
项目类别:
-
资助金额:$30.19万
-
财政年份:1996
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负责人:WILLIAM R SKACH
-
依托单位:
MECHANISMS OF POLYTOPIC PROTEIN BIOGENESIS IN THE ER
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批准号:2192820
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项目类别:
-
资助金额:$22.59万
-
财政年份:1996
-
负责人:WILLIAM R SKACH
-
依托单位:
MECHANISMS OF POLYTOPIC PROTEIN BIOGENESIS IN THE ER
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批准号:6019102
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项目类别:
-
资助金额:$23.81万
-
财政年份:1996
-
负责人:WILLIAM R SKACH
-
依托单位:
BIOGENESIS AND MOLECULAR PATHOGENESIS OF CFTR
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批准号:2838159
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项目类别:
-
资助金额:$21.02万
-
财政年份:1996
-
负责人:WILLIAM R SKACH
-
依托单位:
Mechanisms of Polytopic Protein Biogenesis in the ER
-
批准号:7484130
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项目类别:
-
资助金额:$28.63万
-
财政年份:1996
-
负责人:WILLIAM R SKACH
-
依托单位:
Mechanisms of Polytopic Protein Biogenesis in the ER
-
批准号:7281308
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项目类别:
-
资助金额:$28.63万
-
财政年份:1996
-
负责人:WILLIAM R SKACH
-
依托单位:
Biogenesis and Molecular Pathogenesis of CFTR
-
批准号:7466872
-
项目类别:
-
资助金额:$30.8万
-
财政年份:1996
-
负责人:WILLIAM R SKACH
-
依托单位:
BIOGENESIS AND MOLECULAR PATHOGENESIS OF CFTR
-
批准号:6635075
-
项目类别:
-
资助金额:$26.43万
-
财政年份:1996
-
负责人:WILLIAM R SKACH
-
依托单位:
BIOGENESIS AND MOLECULAR PATHOGENESIS OF CFTR
-
批准号:6517406
-
项目类别:
-
资助金额:$26.43万
-
财政年份:1996
-
负责人:WILLIAM R SKACH
-
依托单位:
Mechanisms of Polyptopic Protein Biogenesis in the ER
-
批准号:7783898
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项目类别:
-
资助金额:$33.11万
-
财政年份:1996
-
负责人:WILLIAM R SKACH
-
依托单位:
BIOGENESIS AND MOLECULAR PATHOGENESIS OF CFTR
-
批准号:2608476
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项目类别:
-
资助金额:$21.91万
-
财政年份:1996
-
负责人:WILLIAM R SKACH
-
依托单位:
BIOGENESIS AND MOLECULAR PATHOGENESIS OF CFTR
-
批准号:6286207
-
项目类别:
-
资助金额:$25.41万
-
财政年份:1996
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负责人:WILLIAM R SKACH
-
依托单位:
Mechanisms of Polyptopic Protein Biogenesis in the ER
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批准号:8286280
-
项目类别:
-
资助金额:$32.78万
-
财政年份:1996
-
负责人:WILLIAM R SKACH
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依托单位:
海外基金