Hic-5, an adaptor-like nuclear receptor coactivator

In recent years, numerous nuclear receptor-interacting proteins have been identified that influence nuclear transcription through their direct modification of chromatin. Along with coactivators that possess histone acetyltransferase (HAT) or methyltransferase activity, other coactivators that lack recognizable chromatin-modifying activity have been discovered whose mechanism of action is largely unknown. The presence of multiple protein-protein interaction motifs within mechanistically undefined coactivators suggests that they function as adaptor molecules, either recruiting or stabilizing promoter-specific protein complexes. This perspective will focus on a family of nuclear receptor coactivators (i.e., group III LIM domain proteins related to paxillin) that appear to provide a scaffold to stabilize receptor interactions with chromatin-modifying coregulators.

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ERAP140, a Conserved Tissue-Specific Nuclear Receptor Coactivator

Molecular and Cellular Biology ◽

10.1128/mcb.22.10.3358-3372.2002 ◽

2002 ◽

Vol 22 (10) ◽

pp. 3358-3372 ◽

Cited By ~ 60

Author(s):

Wenlin Shao ◽

Shlomit Halachmi ◽

Myles Brown

Keyword(s):

Nuclear Receptor ◽

Target Genes ◽

Tissue Type ◽

Interacting Proteins ◽

Nuclear Receptor Coactivator ◽

Nuclear Receptor Coactivators ◽

The Brain ◽

Identification And Characterization

ABSTRACT We report here the identification and characterization of a novel nuclear receptor coactivator, ERAP140. ERAP140 was isolated in a screen for ERα-interacting proteins using the ERα ligand binding domain as a probe. The ERAP140 protein shares no sequence and has little structural homology with other nuclear receptor cofactors. However, homologues of ERAP140 have been identified in mouse, Drosophila, and Caenorhabditis elegans. The expression of ERAP140 is cell and tissue type specific and is most abundant in the brain, where its expression is restricted to neurons. In addition to interacting with ERα, ERAP140 also binds ERβ, TRβ, PPARγ, and RARα. ERAP140 interacts with ERα via a noncanonical interaction motif. The ERα-ERAP140 association can be competed by coactivator NR boxes, indicating ERAP140 binds ERα on a surface similar to that of other coactivators. ERAP140 can enhance the transcriptional activities of nuclear receptors with which it interacts. In vivo, ERAP140 is recruited by estrogen-bound ERα to the promoter region of endogenous ERα target genes. Furthermore, the E2-induced recruitment of ERAP140 to the promoter follows a cyclic pattern similar to that of other coactivators. Our results suggest that ERAP140 represents a distinct class of nuclear receptor coactivators that mediates receptor signaling in specific target tissues.

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Crucial Roles for Interactions between MLL3/4 and INI1 in Nuclear Receptor Transactivation

Molecular Endocrinology ◽

10.1210/me.2008-0455 ◽

2009 ◽

Vol 23 (5) ◽

pp. 610-619 ◽

Cited By ~ 36

Author(s):

Seunghee Lee ◽

Dae-Hwan Kim ◽

Young Hwa Goo ◽

Young Chul Lee ◽

Soo-Kyung Lee ◽

...

Keyword(s):

Nuclear Receptor ◽

Chromatin Remodeling ◽

Target Genes ◽

Mutational Analysis ◽

Specific Protein ◽

Transcriptional Coactivator ◽

Set Domain ◽

Protein Protein Interaction ◽

Terminal Set ◽

Chromatin Remodeling Complex

Abstract Nuclear receptor (NR) transactivation involves multiple coactivators, and the molecular basis for how these are functionally integrated needs to be determined to fully understand the NR action. Activating signal cointegrator-2 (ASC-2), a transcriptional coactivator of many NRs and transcription factors, forms a steady-state complex, ASCOM (for ASC-2 complex), which contains histone H3-lysine-4 (H3K4) methyltransferase MLL3 or its paralog MLL4. Here, we show that ASCOM requires a functional cross talk with the ATPase-dependent chromatin remodeling complex Swi/Snf for efficient NR transactivation. Our results reveal that ASCOM and Swi/Snf are tightly colocalized in the nucleus and that ASCOM and Swi/Snf promote each other’s binding to NR target genes. We further show that the C-terminal SET domain of MLL3 and MLL4 directly interacts with INI1, an integral subunit of Swi/Snf. Our mutational analysis demonstrates that this interaction underlies the mutual facilitation of ASCOM and Swi/Snf recruitment to NR target genes. Importantly, this study uncovers a specific protein-protein interaction as a novel venue to couple two distinct enzymatic coactivator complexes during NR transactivation.

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A New Method for Recognizing Protein Complexes Based on Protein Interaction Networks and GO Terms

Frontiers in Genetics ◽

10.3389/fgene.2021.792265 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiaoting Wang ◽

Nan Zhang ◽

Yulan Zhao ◽

Juan Wang

Keyword(s):

Protein Interaction ◽

Protein Complexes ◽

Protein Interaction Networks ◽

New Method ◽

Protein Protein Interaction ◽

Evolution Analysis ◽

Ppi Networks ◽

Multiple Protein ◽

Topology Information ◽

Go Terms

Motivation: A protein complex is the combination of proteins which interact with each other. Protein–protein interaction (PPI) networks are composed of multiple protein complexes. It is very difficult to recognize protein complexes from PPI data due to the noise of PPI.Results: We proposed a new method, called Topology and Semantic Similarity Network (TSSN), based on topological structure characteristics and biological characteristics to construct the PPI. Experiments show that the TSSN can filter the noise of PPI data. We proposed a new algorithm, called Neighbor Nodes of Proteins (NNP), for recognizing protein complexes by considering their topology information. Experiments show that the algorithm can identify more protein complexes and more accurately. The recognition of protein complexes is vital in research on evolution analysis.Availability and implementation: https://github.com/bioinformatical-code/NNP.

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Ubiquitin-specific protease 8 (USP8/UBPy): a prototypic multidomain deubiquitinating enzyme with pleiotropic functions

Biochemical Society Transactions ◽

10.1042/bst20190527 ◽

2019 ◽

Vol 47 (6) ◽

pp. 1867-1879 ◽

Cited By ~ 4

Author(s):

Almut Dufner ◽

Klaus-Peter Knobeloch

Keyword(s):

T Cell ◽

Protein Modification ◽

Catalytic Domain ◽

Protein Complexes ◽

Specific Protein ◽

Protein Protein Interaction ◽

Specific Protease ◽

Ubiquitin Specific Protease ◽

Associated Function ◽

And Function

Protein modification by ubiquitin is one of the most versatile posttranslational regulations and counteracted by almost 100 deubiquitinating enzymes (DUBs). USP8 was originally identified as a growth regulated ubiquitin-specific protease and is like many other DUBs characterized by its multidomain architecture. Besides the catalytic domain, specific protein–protein interaction modules were characterized which contribute to USP8 substrate recruitment, regulation and targeting to distinct protein complexes. Studies in mice and humans impressively showed the physiological relevance and non-redundant function of USP8 within the context of the whole organism. USP8 knockout (KO) mice exhibit early embryonic lethality while induced deletion in adult animals rapidly causes lethal liver failure. Furthermore, T-cell specific ablation disturbs T-cell development and function resulting in fatal autoimmune inflammatory bowel disease. In human patients, somatic mutations in USP8 were identified as the underlying cause of adrenocorticotropic hormone (ACTH) releasing pituitary adenomas causing Cushing's disease (CD). Here we provide an overview of the versatile molecular, cellular and pathology associated function and regulation of USP8 which appears to depend on specific protein binding partners, substrates and the cellular context.

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