Involvement of Smi1 in cell wall integrity and glucan synthase Bgs4 localization during fission yeast cytokinesis

Cytokinesis is the final step of the cell-division cycle. In fungi, it relies on the coordination of constriction of an actomyosin contractile ring and construction of the septum at the division site. Glucan synthases synthesize glucans, which are the major components in fungal cell walls and division septa. It is known that Rho1 and Rho2 GTPases regulate glucan synthases Bgs1, Bgs4, and Ags1, and Sbg1 and the F-BAR protein Cdc15 play roles in Bgs1 stability and delivery to the plasma membrane. Here we characterize Smi1, an intrinsically disordered protein that interacts with Bgs4 and regulates its trafficking and localization in fission yeast. Smi1 is important for septum integrity, and its absence causes severe lysis during cytokinesis. Smi1 localizes to secretory vesicles and moves together with Bgs4 towards the division site. The concentrations of the glucan synthases Bgs1 and Bgs4 and the glucanases Agn1 and Bgl2 decrease at the division site in smi1 mutant, but Smi1 seems to be more specific to Bgs4. Mistargeting of Smi1 to mitochondria mislocalizes Bgs4, but not Bgs1. Together, our data reveal a novel regulator of glucan synthases and glucanases, Smi1, which is more important for Bgs4 trafficking, stability, and localization during cytokinesis. [Media: see text] [Media: see text]

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Self-Assembling Micelles Based on an Intrinsically Disordered Protein Domain

10.26434/chemrxiv.7157507 ◽

2018 ◽

Author(s):

Sarah Klass ◽

Matthew J. Smith ◽

Tahoe Fiala ◽

Jessica Lee ◽

Anthony Omole ◽

...

Keyword(s):

Drug Delivery ◽

Fusion Proteins ◽

Organic Molecules ◽

Intrinsically Disordered Protein ◽

Protein Domain ◽

Enzymatic Cleavage ◽

Intrinsically Disordered ◽

Disordered Protein ◽

Self Assembling ◽

Protein Tag

Herein, we describe a new series of fusion proteins that have been developed to self-assemble spontaneously into stable micelles that are 27 nm in diameter after enzymatic cleavage of a solubilizing protein tag. The sequences of the proteins are based on a human intrinsically disordered protein, which has been appended with a hydrophobic segment. The micelles were found to form across a broad range of pH, ionic strength, and temperature conditions, with critical micelle concentration (CMC) values below 1 µM being observed in some cases. The reported micelles were found to solubilize hydrophobic metal complexes and organic molecules, suggesting their potential suitability for catalysis and drug delivery applications.

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Faculty Opinions recommendation of Osmolyte-induced folding of an intrinsically disordered protein: folding mechanism in the absence of ligand.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.4040956.3812054 ◽

2010 ◽

Author(s):

Kunihiro Kuwajima

Keyword(s):

Protein Folding ◽

Intrinsically Disordered Protein ◽

Intrinsically Disordered ◽

Disordered Protein ◽

Folding Mechanism ◽

Induced Folding

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Faculty Opinions recommendation of Folding of an intrinsically disordered protein by phosphorylation as a regulatory switch.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725287895.793508986 ◽

2015 ◽

Author(s):

Athi N Naganathan

Keyword(s):

Intrinsically Disordered Protein ◽

Intrinsically Disordered ◽

Disordered Protein

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Faculty Opinions recommendation of Folding of an intrinsically disordered protein by phosphorylation as a regulatory switch.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725287895.793503118 ◽

2015 ◽

Author(s):

Wolfgang Peti ◽

Michael Clarkson

Keyword(s):

Intrinsically Disordered Protein ◽

Intrinsically Disordered ◽

Disordered Protein

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Faculty Opinions recommendation of Rapid evolution of virus sequences in intrinsically disordered protein regions.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725276205.793502624 ◽

2014 ◽

Author(s):

Vladimir Uversky

Keyword(s):

Rapid Evolution ◽

Intrinsically Disordered Protein ◽

Intrinsically Disordered ◽

Disordered Protein

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Mutations of Intrinsically Disordered Protein Regions Can Drive Cancer but Lack Therapeutic Strategies

Biomolecules ◽

10.3390/biom11030381 ◽

2021 ◽

Vol 11 (3) ◽

pp. 381

Author(s):

Bálint Mészáros ◽

Borbála Hajdu-Soltész ◽

András Zeke ◽

Zsuzsanna Dosztányi

Keyword(s):

Gene Expression Regulation ◽

Treatment Options ◽

Intrinsically Disordered Protein ◽

System Level ◽

Alternative Mechanism ◽

Intrinsically Disordered ◽

Intrinsically Disordered Regions ◽

Disordered Protein ◽

Cancer Types ◽

Cancer Drivers

Many proteins contain intrinsically disordered regions (IDRs) which carry out important functions without relying on a single well-defined conformation. IDRs are increasingly recognized as critical elements of regulatory networks and have been also associated with cancer. However, it is unknown whether mutations targeting IDRs represent a distinct class of driver events associated with specific molecular and system-level properties, cancer types and treatment options. Here, we used an integrative computational approach to explore the direct role of intrinsically disordered protein regions driving cancer. We showed that around 20% of cancer drivers are primarily targeted through a disordered region. These IDRs can function in multiple ways which are distinct from the functional mechanisms of ordered drivers. Disordered drivers play a central role in context-dependent interaction networks and are enriched in specific biological processes such as transcription, gene expression regulation and protein degradation. Furthermore, their modulation represents an alternative mechanism for the emergence of all known cancer hallmarks. Importantly, in certain cancer patients, mutations of disordered drivers represent key driving events. However, treatment options for such patients are currently severely limited. The presented study highlights a largely overlooked class of cancer drivers associated with specific cancer types that need novel therapeutic options.

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Mediator subunit Med15 dictates the conserved “fuzzy” binding mechanism of yeast transcription activators Gal4 and Gcn4

Nature Communications ◽

10.1038/s41467-021-22441-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Lisa M. Tuttle ◽

Derek Pacheco ◽

Linda Warfield ◽

Damien B. Wilburn ◽

Steven Hahn ◽

...

Keyword(s):

Intrinsically Disordered Protein ◽

Activation Function ◽

Binding Mechanism ◽

Binding Partner ◽

Protein Protein Interaction ◽

Intrinsically Disordered ◽

Disordered Protein ◽

Independent Mechanism ◽

Transcription Activators ◽

Common Sequence

AbstractThe acidic activation domain (AD) of yeast transcription factor Gal4 plays a dual role in transcription repression and activation through binding to Gal80 repressor and Mediator subunit Med15. The activation function of Gal4 arises from two hydrophobic regions within the 40-residue AD. We show by NMR that each AD region binds the Mediator subunit Med15 using a “fuzzy” protein interface. Remarkably, comparison of chemical shift perturbations shows that Gal4 and Gcn4, two intrinsically disordered ADs of different sequence, interact nearly identically with Med15. The finding that two ADs of different sequence use an identical fuzzy binding mechanism shows a common sequence-independent mechanism for AD-Mediator binding, similar to interactions within a hydrophobic cloud. In contrast, the same region of Gal4 AD interacts strongly with Gal80 via a distinct structured complex, implying that the structured binding partner of an intrinsically disordered protein dictates the type of protein–protein interaction.

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