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E2泛素结合酶9（UBC9）介导的磷酸化依赖性小泛素样修饰蛋白（SUMO）缀合的分子基础

A molecular basis for phosphorylation-dependent SUMO conjugation by the E2 UBC9.

作者信息

Mohideen Firaz, Capili Allan D, Bilimoria Parizad M, Yamada Tomoko, Bonni Azad, Lima Christopher D

机构信息

Program in Structural Biology, Sloan-Kettering Institute, New York, New York, USA.

出版信息

Nat Struct Mol Biol. 2009 Sep;16(9):945-52. doi: 10.1038/nsmb.1648. Epub 2009 Aug 16.

DOI:10.1038/nsmb.1648
PMID:19684601
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2771680/
Abstract

Phosphorylation and small ubiquitin-like modifier (SUMO) conjugation contribute to the spatial and temporal regulation of substrates containing phosphorylation-dependent SUMO consensus motifs (PDSMs). Myocyte-enhancement factor 2 (MEF2) is a transcription factor and PDSM substrate whose modification by SUMO drives postsynaptic dendritic differentiation. NMR analysis revealed that the human SUMO E2 interacted with model substrates for phosphorylated and nonphosphorylated MEF2 in similar extended conformations. Mutational and biochemical analysis identified a basic E2 surface that enhanced SUMO conjugation to phosphorylated PDSM substrates MEF2 and heat-shock transcription factor 1 (HSF1), but not to nonphosphorylated MEF2 or HSF1, nor the non-PDSM substrate p53. Mutant ubiquitin-conjugating enzyme UBC9 isoforms defective in promoting SUMO conjugation to phosphorylated MEF2 in vitro and in vivo also impair postsynaptic differentiation in organotypic cerebellar slices. These data support an E2-dependent mechanism that underlies phosphorylation-dependent SUMO conjugation in pathways that range from the heat-shock response to nuclear hormone signaling to brain development.

摘要

磷酸化和小泛素样修饰物（SUMO）缀合作用有助于对含有磷酸化依赖性SUMO共有基序（PDSM）的底物进行空间和时间调控。肌细胞增强因子2（MEF2）是一种转录因子和PDSM底物，其SUMO修饰驱动突触后树突分化。核磁共振分析表明，人SUMO E2以相似的伸展构象与磷酸化和非磷酸化MEF2的模型底物相互作用。突变和生化分析确定了一个碱性E2表面，该表面增强了SUMO与磷酸化PDSM底物MEF2和热休克转录因子1（HSF1）的缀合，但不增强与非磷酸化MEF2或HSF1以及非PDSM底物p53的缀合。在体外和体内促进SUMO与磷酸化MEF2缀合存在缺陷的突变泛素缀合酶UBC9同工型，也会损害小脑器官型切片中的突触后分化。这些数据支持了一种E2依赖性机制，该机制是从热休克反应到核激素信号传导再到脑发育等途径中磷酸化依赖性SUMO缀合的基础。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6261/2771680/cbe297065d67/nihms-129304-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6261/2771680/190a6ce721c7/nihms-129304-f0001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6261/2771680/02d39eb09c5c/nihms-129304-f0003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6261/2771680/cbe297065d67/nihms-129304-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6261/2771680/190a6ce721c7/nihms-129304-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6261/2771680/a44f84ba140c/nihms-129304-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6261/2771680/02d39eb09c5c/nihms-129304-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6261/2771680/7653ad0fcdcd/nihms-129304-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6261/2771680/381a966c1704/nihms-129304-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6261/2771680/cbe297065d67/nihms-129304-f0006.jpg

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