MOLECULAR ARCHITECTURES OF BTB-CUL3 UBIQUITIN LIGASES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 目前了解最多的是Clolin环E3泛素连接酶(CRL)，它是一种SCF泛素连接酶，由Cul1、Skp1和F-box家族的成员组成。Skp1作为一个接头，同时结合Cul1的N-末端附近的序列和F-box蛋白的F-box基序。反过来，F-box蛋白包含额外的蛋白质相互作用结构域，将底物招募到Cul1-Skp1-F-box蛋白复合体中，从而通过组装在cul1的C-末端的催化核心促进靶标的泛素化。相反，CUL3使用BTB蛋白作为底物特异性适配器。“BTB”是一个蛋白质相互作用/二聚结构域，在结构上与Skp1的cullin结合区同源，并通过与Skp1-Cul1复合体中类似的基序与CUL3结合。许多BTB结构域蛋白还包含额外的蛋白质相互作用结构域，其中一些已被证明招募泛素化靶标。因此，BTB蛋白被认为将Skp1或EloC及其F-box或SoCS-box伴侣的功能特性合并到一个单一的多肽链中，而不存在F-或SoCS-box。 人类基因组编码150多种蛋白质，具有可识别的BTB结构域，通常与MATH、Kelch或其他相互作用结构域结合在一起。含有Math和Kelch结构域的BTB蛋白与CUL3靶向底物有关，尽管目前尚不清楚体内有多少BTB蛋白与CUL3结合。此外，关于数学领域如何选择CRL泛素化的目标也知之甚少。数学结构域存在于众多不同的蛋白质中，最常被发现与C-末端的BTB结构域相连。事实上，MATH-BTB模块是由131个基因组编码的两个结构域组合中第十丰富的。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The best understood Cullin-RING E3 ubiquitin ligase (CRL) is the SCF ubiquitin ligase, composed of Cul1, Skp1 and a member of the F-box family of proteins. Skp1 serves as an adaptor that simultaneously binds sequences near the N-terminus of Cul1 and the F-box motif of an F-box protein. In turn, F-box proteins contain additional protein interaction domains that recruit the substrate into a Cul1-Skp1-F-box protein complex, thereby facilitating ubiquitination of the target via the catalytic core assembled on the C-terminus of Cul1. In contrast, Cul3 employs BTB proteins as substrate specific adaptor. "BTB" is a protein interaction/dimerization domain that is structurally homologous to the cullin-binding region of Skp1, and that binds Cul3 via motifs analogous to those in the Skp1-Cul1 complex. Many BTB-domain proteins also contain additional protein interaction domains, some of which have been shown to recruit ubiquitination targets. Thus, BTB proteins are thought to merge the functional properties of Skp1or EloC and their F-box or SOCS-box partners into a single polypeptide chain, without an intervening F- or SOCS- box. The human genome encodes more than 150 proteins with recognizable BTB domains, often in combination with MATH, Kelch, or other interaction domains. BTB proteins containing MATH and Kelch domains have been linked to substrate targeting by Cul3, although it is unclear precisely how many BTB proteins engage Cul3 in vivo. Also, little is known about how MATH domains select targets for ubiquitination by CRLs. The MATH domain, present in numerous diverse proteins, is most frequently found linked to a C-terminal BTB domain. Indeed, the MATH-BTB module is the 10th most abundant of 2-domain combinations encoded by 131 genomes.