biology

Protein inhibitor of activated STAT

Protein inhibitor of activated STAT is a biology topic covered in the lgStudy science library. This page brings together a partial reference excerpt, illustrations, worked examples, real-world applications and a short study plan, so you can understand Protein inhibitor of activated STAT rather than just read about it. In short: Protein inhibitor of activated STAT (PIAS), also known as E3 SUMO-protein ligase PIAS, is a protein that regulates transcription in mammals. PIAS proteins act as transcriptional co-regulators with at least 60 different proteins in order to either activate or repress transcription.

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Reference excerpt

Protein inhibitor of activated STAT (PIAS), also known as E3 SUMO-protein ligase PIAS, is a protein that regulates transcription in mammals. PIAS proteins act as transcriptional co-regulators with at least 60 different proteins in order to either activate or repress transcription. The transcription factors STAT, NF-κB, p73, and p53 are among the many proteins that PIAS interacts with. The seven proteins that belong to the mammalian PIAS family are encoded by four genes: PIAS1, PIAS2 (PIASx), PIAS3, and PIAS4 (PIASy). Apart from PIAS1, each gene encodes two protein isoforms. Homologues of PIAS proteins have been found in other eukaryotes, including Zimp/dPIAS in Drosophila melanogaster and zfPIAS4a in zebrafish. SIZ1 and SIZ2 were two homologues identified in yeast. PIAS proteins contain each conserved domain and motif of the PIAS protein family, with a few exceptions. The known functions of these domains and motifs are similar among all PIAS protein family members. These functions include acting as E3 SUMO-protein ligases during SUMOylation, which is an important process in transcriptional regulation. Presently, less is known about the higher order structure of PIAS proteins. The three-dimensional protein structures of PIAS2, PIAS3, and SIZ1 have only recently been solved. PIAS proteins have potential applications in cancer treatment and prevention. They may also play an important role in regulating immune system responses.

Discovery The discovery of PIAS3 was first published in 1997. The discovery was made while the JAK-STAT pathway was being studied. The discovery of other PIAS proteins, including PIAS1, PIASxα, PIASxβ, and PIASy, was published the following year. The interaction between STATs and PIASs was characterized by the yeast two-hybrid assay. PIAS proteins were named based on their ability to inhibit STAT. For example, PIAS1 inhibited STAT1, and PIAS3 inhibited STAT3. When it was discovered that PIAS proteins did far more than simply inhibit STATs, it was proposed that the PIAS acronym should stand for Pleiotropic Interactors Associated with SUMO based on their association with SUMO proteins. Additionally, E3 SUMO-protein ligase PIAS is an alternative name for PIAS proteins. The discovery of PIAS3L, an isoform of PIAS3, was published in 2003. In addition, the discovery of PIASyE6- was published in 2004. It is an isoform of PIASy that doesn't contain exon 6.

Types of PIAS proteins

The table below lists the seven known proteins that belong to the mammalian PIAS protein family. Due to alternative splicing, some PIAS protein-encoding genes encode multiple protein products called isoforms. PIAS1 is the only gene of this family that does not encode any isoforms.

Homologues Homologues of PIAS proteins have been found in other eukaryotes, and several are listed below:

Zimp/dPIAS in Drosophila melanogaster zfPIAS4a in zebrafish SIZ1 and SIZ2 in yeast

Function PIAS proteins contribute to the control of gene expression, and may be considered transcriptional co-regulators. While PIAS proteins interact with at least 60 different proteins involved in transcription, they are known to act as E3 SUMO-protein ligases. In essence, the RING-finger-like zinc-binding domain of the PIAS protein assists in the attachment of a SUMO protein to the target transcription factor. Attachment of a SUMO protein to the target allows for protein–protein interaction between PIAS and the transcription factor. This interaction can either upregulate or downregulate transcription. For example, the activity of transcription factor p73 was repressed after it was SUMOylated by PIAS1. One function of PIAS proteins is to relocate transcriptional regulators to different compartments within the nucleus of the cell. PIAS proteins also play a key role in double-stranded break DNA repair. Exposure to UV light, chemicals, and ionizing radiation can cause DNA damage, and the most detrimental type of DNA damage is a double-stranded break. PIAS1, PIAS3, and PIAS4 have been shown to recruit proteins to the site of the damage and promote repair. Additionally, PIAS proteins are important transcriptional co-regulators of the JAK/STAT signaling pathway. PIAS protein's interaction with STAT signaling requires tyrosine phosphorylation of STAT proteins. Additionally, PIAS1 binds preferentially to un-methylated STAT1. Although the exact mechanism isn't clear, PIAS1 and PIASy both inhibit STAT1 signaling. PIAS3 was found to specifically inhibit STAT3 signaling after stimulation by the cytokine IL-6. Also, it is known that PIAS1 can inhibit NF-κB activity upon stimulation by the cytokine TNF and the LPS endotoxin.

Structure

The three-dimensional protein structures of PIAS2, PIAS3, and PIAS-like protein SIZ1 were recently solved using X-ray crystallography. The structures of PIAS2 and PIAS3 were listed in the Structural Genomics Consortium in 2012 and 2013, respectively, by A. Dong et al. Details of the SIZ1 structure were published by Ali A. Yunus and Christopher D. Lima in 2009. Four PIAS domains and two PIAS motifs have been identified. They include the N-terminal scaffold attachment factor-A/B, acinus and PIAS (SAP) domain, the Pro-Ile-Asn-Ile-Thr (PINIT) motif, the RING-finger-like zinc-binding domain (RLD), the highly acidic domain (AD), the SUMO-interacting motif (SIM), and the serine/threonine-rich C-terminal region (S/T).

SAP

The N-terminal scaffold attachment factor-A/B, acinus and PIAS (SAP) domain is found in all PIAS proteins. It is composed of four alpha helices. It binds to areas of chromatin that are rich in adenine (A) and thymine (T). These A/T rich regions are known as matrix-attachment regions. Once bound, the matrix-attachment regions anchor loops of chromatin to the nuclear matrix. The nuclear matrix is a structure within the nucleus where it is thought that transcription regulation takes place. SAP also binds to p53. Each SAP domain contains an LXXLL amino acid motif. L = leucine, and X = any amino acid. This motif is used to bind to nuclear receptors. Nuclear receptors are transcription factors that regulate transcription upon ligand binding.

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Worked examples

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Example 2 — changing one variable

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Example 3 — an exam-style question

Typical questions about Protein inhibitor of activated STAT ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of Protein inhibitor of activated STAT

In research: Protein inhibitor of activated STAT appears in biology research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses Protein inhibitor of activated STAT in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: Protein inhibitor of activated STAT is common in secondary-school and first-year university syllabi. It links to neighbouring topics Cell signaling, Proteins, so understanding it makes those chapters shorter.
In everyday life: Look for Protein inhibitor of activated STAT outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

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