A5051835645- Microtubule and mitosis dynamics
- Ubiquitin and proteasome pathways
- Cancer-related Molecular Pathways
- Fungal and yeast genetics research
- Genomics and Chromatin Dynamics
- RNA and protein synthesis mechanisms
- DNA Repair Mechanisms
- RNA Research and Splicing
- CRISPR and Genetic Engineering
- Protein Structure and Dynamics
- SARS-CoV-2 and COVID-19 Research
- Animal Virus Infections Studies
- Protein Kinase Regulation and GTPase Signaling
- Plant nutrient uptake and metabolism
- Endoplasmic Reticulum Stress and Disease
- Virus-based gene therapy research
- 14-3-3 protein interactions
- Genetics and Neurodevelopmental Disorders
- Mass Spectrometry Techniques and Applications
- Cellular transport and secretion
- Advanced Proteomics Techniques and Applications
- Enzyme Structure and Function
- Plant Molecular Biology Research
- Mitochondrial Function and Pathology
- Photosynthetic Processes and Mechanisms
University of Cambridge
2024-2025
Institute of Cancer Research
2021-2025
Cancer Research UK
2025
Cancer Research UK Cambridge Center
2024
University of Tartu
2013-2023
Abstract Almost twenty years after its initial release, the Eukaryotic Linear Motif (ELM) resource remains an invaluable source of information for study motif-mediated protein-protein interactions. ELM provides a comprehensive, regularly updated and well-organised repository manually curated, experimentally validated short linear motifs (SLiMs). An increasing number SLiM-mediated interactions are discovered each year keeping up-to-date continues to be great challenge. In current update, 30...
Abstract The Spike protein of the novel coronavirus SARS-CoV2 contains an insertion 680 S PRRA R↓SV 687 forming a cleavage motif RxxR for furin-like enzymes at boundary S1/S2 subunits. Cleavage is important efficient viral entry into target cells. absent in other CoV-s same clade, including SARS-CoV1 that caused 2003 outbreak. However, analogous was present more distant Middle East Respiratory Syndrome MERS-CoV. We show crucial third arginine left middle position, comprising R xR required...
Cyclin-dependent kinases (CDKs) coordinate hundreds of molecular events during the cell cycle. Multiple cyclins are involved, but global role cyclin-specific phosphorylation has remained unsolved. We uncovered a cyclin docking motif, LxF, that mediates binding replication factor Cdc6 to mitotic cyclin. This interaction leads phospho-adaptor Cks1-mediated inhibition M-CDK facilitate accumulation and sequestration in mitosis. The LxF motif Cks1 also mediate mutual between tyrosine kinase Swe1....
Multisite phosphorylation of proteins is a powerful signal processing mechanism that plays crucial roles in cell division and differentiation as well disease. We recently demonstrated novel phenomenon cycle regulation by showing cyclin-dependent kinase-dependent multisite substrate performed sequentially the N-to-C terminal direction along disordered protein. The process controlled key parameters, including distance between sites, distribution serines threonines position docking motifs....
Eukaryotic cell division has been studied thoroughly and is understood in great mechanistic detail. Paradoxically, however, we lack an understanding of its core control process, which the master regulator cycle, cyclin-dependent kinase (CDK), temporally coordinates array complex molecular events. The elements CDK system are conserved eukaryotic cells, contain multiple cyclin-CDK forms that have poorly defined partially overlapping responsibilities cycle. However, a single can drive all...
Article19 November 2020Open Access Source DataTransparent process A new linear cyclin docking motif that mediates exclusively S-phase CDK-specific signaling Ilona Faustova Institute of Technology, University Tartu, Estonia Search for more papers by this author Luka Bulatovic Frida Matiyevskaya Ervin Valk Mihkel Örd Mart Loog Corresponding Author [email protected] orcid.org/0000-0003-1330-8453 Information Faustova1, Bulatovic1, Matiyevskaya1, Valk1, Örd1 and *,1 1Institute *Corresponding...
The hydrophobic patch (hp), a docking pocket on cyclins of CDKs (cyclin-dependent kinases), has been thought to accommodate single short linear motif (SLiM), the "RxL or Cy" motif. Here we show that hp can bind different motifs with high specificity. We identify PxxPxF is necessary for G2-cyclin Clb3 function in S. cerevisiae, and mediates Clb3-Cdk1 phosphorylation Ypr174c (proposed name: Cdc5 SPB anchor-Csa1) regulate localization Polo kinase Cdc5. Similar exist other targets. Our work...
Abstract Protein phosphorylation enables a rapid adjustment of cellular activities to diverse intracellular and environmental stimuli. Many phosphoproteins are targeted on more than one site, which allows the integration multiple signals implementation complex responses. However, hierarchy interplay between phospho-sites often unknown. Here, we study multi‐site using yeast trehalase Nth1 its activator, 14-3-3 protein Bmh1, as model. is known be phosphorylated by metabolic kinase PKA four...
Abstract Studies on multisite phosphorylation networks of cyclin-dependent kinase (CDK) targets have opened a new level signaling complexity by revealing signal processing routes encoded into disordered proteins. A model target, the CDK inhibitor Sic1, contains linear motifs, docking sites, and phosphodegrons to empower an N-to-C terminally directed process. Here, we uncover mechanism involving multi-step competition between mutually diversional within S-CDK-Sic1 inhibitory complex....
The complexity of multisite phosphorylation mechanisms in regulating nuclear localization signals (NLSs) and export (NESs) is not understood, its potential has been used synthetic biology. nucleocytoplasmic shuttling many proteins regulated by cyclin-dependent kinases (CDKs) that rely on patterns short linear motifs (SLiMs) to dynamically control the cell cycle. We studied role motif using sensors based CDK targets Dna2, Psy4, Mcm2/3 Saccharomyces cerevisiae. designed modules rearranging...
Abstract Phos-tag TM SDS-PAGE is a method that enables electrophoretic separation of proteins based on their phosphorylation status. With SDS-PAGE, it possible to discriminate between different phosphoforms level and the number phosphorylated sites, determine stoichiometry products. useful for analyzing disordered with multiple sites can be used any downstream applications in combination conventional example, Western blotting mass-spectrometry. To obtain best results however, often necessary...
ABSTRACT Transient protein-protein interactions play key roles in controlling dynamic cellular responses. Many examples involve globular protein domains that bind to peptide sequences known as Short Linear Motifs (SLiMs), which are enriched intrinsically disordered regions of proteins. Here we describe a novel functional assay for measuring SLiM binding, called Systematic Intracellular Motif Binding Analysis (SIMBA). In this method, binding foreign domain its cognate allows yeast cells...
Cdc6, a subunit of the pre-replicative complex (pre-RC), contains multiple regulatory cyclin-dependent kinase (Cdk1) consensus sites, SP or TP motifs. In Saccharomyces cerevisiae, Cdk1 phosphorylates Cdc6-T7 to recruit Cks1, phospho-adaptor in S phase, for subsequent multisite phosphorylation and protein degradation. Cdc6 accumulates mitosis is tightly bound by Clb2 through N-terminal order prevent premature origin licensing It has been extensively studied how regulated cyclin-Cdk1 complex....
Kinetochores are multi-subunit protein assemblies that link chromosomes to microtubules of the mitotic and meiotic spindle. It is still poorly understood how efficient, centromere-dependent kinetochore assembly accomplished from hundreds individual building blocks in a cell cycle-dependent manner. Here, by combining comprehensive phosphorylation analysis native Ctf19CCAN subunits with biochemical functional assays model system budding yeast, we demonstrate Cdk1 activates phospho-degrons on...
Abstract The Spike protein of the novel coronavirus SARS-CoV2 contains an insertion 680 S PRRA R↓SV 687 forming a cleavage motif RxxR for furin-like enzymes at boundary S1/S2 subunits. Cleavage is important efficient viral entry into target cells. absent in other CoV-s same clade, including SARS-CoV1 that caused 2003 outbreak. However, analogous was present more distant Middle East Respiratory Syndrome MERS-CoV. We show crucial third arginine left middle position, comprising R xR required...
Cyclin-CDKs are master regulators of cell division. In addition to directly activating the CDK, cyclin subunit regulates CDK specificity by binding short peptide "docking" motifs in substrates. Here, we measure relative strength ∼100,000 peptides 11 human cyclins from five families (D, E, A, B and F). Using a quantitative intracellular assay large-scale tiled screening, identified range non-canonical binders that unveil broader than anticipated repertoire docking motif types. Structural...
Cyclins are the activators of cyclin-dependent kinase (CDK) complex, but they also act as docking scaffolds for different short linear motifs (SLiMs) in CDK substrates and inhibitors. According to unified model function, cell cycle is coordinated by both via general activity thresholds cyclin-specific substrate docking. Recently, it was found that G1-cyclins S. cerevisiae have a specific function promoting polarization growth buds, making G1 cyclins essential survival. Thus, while uniform...
Abstract Protein phosphorylation enables a rapid adjustment of cellular activities to diverse intracellular and environmental stimuli. Many phosphoproteins are targeted on more than one site, which allows the integration multiple signals implementation complex responses. However, hierarchy interplay between phospho-sites often unknown. Here, we study multi-site using yeast trehalase Nth1 its activator, 14-3-3 protein Bmh1, as model. is known be phosphorylated by metabolic kinase PKA four...
Summary Cell-cycle progression is driven by the phosphorylation of cyclin-dependent kinase (Cdk) substrates 1–3 . The order substrate depends in part on general rise Cdk activity during cell cycle 4–7 , together with variations docking to sites associated cyclin and Cks subunits 3, 6, 8–10 Many are modified at multiple provide more complex regulation 9, 11–14 Here, we describe an elegant regulatory circuit based multisite Ndd1, a transcriptional co-activator genes required for mitotic 15, 16...