Ville Paavilainen

Ville Paavilainen
University of Helsinki | HY · Institute of Biotechnology

Doctor of Philosophy

About

44
Publications
6,894
Reads
How we measure 'reads'
A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors), clicks on a figure, or views or downloads the full-text. Learn more
2,120
Citations
Citations since 2017
23 Research Items
1126 Citations
2017201820192020202120222023050100150200250
2017201820192020202120222023050100150200250
2017201820192020202120222023050100150200250
2017201820192020202120222023050100150200250
Additional affiliations
February 2014 - present
University of Helsinki
Position
  • Tenure Track Group Leader
March 2008 - February 2014
University of California, San Francisco
Position
  • PostDoc Position
January 2001 - February 2008
University of Helsinki
Position
  • PostDoc Position

Publications

Publications (44)
Article
Full-text available
Mycolactone, an immunosuppressive macrolide released by the human pathogen Mycobacterium ulcerans, was previously shown to impair Sec61-dependent protein translocation, but the underlying molecular mechanism was not identified. In this study, we show that mycolactone directly targets the α subunit of the Sec61 translocon to block the production of...
Article
Apratoxin A is a cytotoxic natural product that prevents the biogenesis of secretory and membrane proteins. Biochemically, apratoxin A inhibits cotranslational translocation into the ER, but its cellular target and mechanism of action have remained controversial. Here, we demonstrate that apratoxin A prevents protein translocation by directly targe...
Article
Full-text available
Drugs with prolonged on-target residence times often show superior efficacy, yet general strategies for optimizing drug-target residence time are lacking. Here we made progress toward this elusive goal by targeting a noncatalytic cysteine in Bruton's tyrosine kinase (BTK) with reversible covalent inhibitors. Using an inverted orientation of the cys...
Article
Full-text available
Actin dynamics provide the driving force for many cellular processes including motility and endocytosis. Among the central cytoskeletal regulators are actin-depolymerizing factor (ADF)/cofilin, which depolymerizes actin filaments, and twinfilin, which sequesters actin monomers and caps filament barbed ends. Both interact with actin through an ADF h...
Article
A stop codon within the mRNA facilitates coordinated termination of protein synthesis, releasing the nascent polypeptide from the ribosome. This essential step in gene expression is impeded with transcripts lacking a stop codon, generating nonstop ribosome complexes. Here, we use deep sequencing to investigate sources of nonstop mRNAs generated fro...
Preprint
Full-text available
Protein translocation across the endoplasmic reticulum (ER) membrane is an essential initial step in protein entry into the secretory pathway. The conserved Sec61 protein translocon facilitates polypeptide translocation and coordinates cotranslational polypeptide processing events. In cells, the majority of Sec61 is stably associated with a heterot...
Preprint
Preventing the biogenesis of disease-relevant proteins is an attractive therapeutic strategy, but attempts to target essential protein biogenesis factors have been hampered by excessive toxicity. Here, we describe KZR-8445, a cyclic depsipeptide that targets the Sec61 translocon and selectively disrupts secretory and membrane protein biogenesis in...
Preprint
Signal peptides are short amino acid segments present at the N-terminus of newly synthesized proteins that facilitate protein translocation into the lumen of the endoplasmic reticulum, after which they are cleaved off. Specific regions of signal peptides influence the efficiency of protein translocation, and small changes in their primary structure...
Article
Full-text available
The integrity of a cell’s proteome depends on correct folding of polypeptides by chaperonins. The chaperonin TCP-1 ring complex (TRiC) acts as obligate folder for >10% of cytosolic proteins, including he cytoskeletal proteins actin and tubulin. Although its architecture and how it recognizes folding substrates are emerging from structural studies,...
Preprint
Full-text available
The integrity of a cell's proteome depends on correct folding of polypeptides by chaperonins. The TCP-1 ring chaperonin (TRiC) acts as obligate folder for >10% of cytosolic proteins, including cytoskeletal proteins actin and tubulin. While its architecture and how it recognises folding substrates is emerging from structural studies, the subsequent...
Article
Full-text available
Intracellular pH is a potent modulator of neuronal functions. By catalyzing (de)hydration of CO2 , intracellular carbonic anhydrase (CAi ) isoforms CA2 and CA7 contribute to neuronal pH buffering and dynamics. The presence of two highly active isoforms in neurons suggests that they may serve isozyme-specific functions unrelated to CO2 -(de)hydratio...
Article
Full-text available
Targeting of HER/ErbB family proteins using broad spectrum Sec61 inhibitors coibamide A and apratoxin A, Biochemical Pharmacology (2020), doi: https://doi. Abstract Coibamide A is a potent cancer cell toxin and one of a select group of natural products that inhibit protein entry into the secretory pathway via a direct inhibition of the Sec61 protei...
Article
Full-text available
Coibamide A (CbA) is a marine natural product with potent antiproliferative activity against human cancer cells and a unique selectivity profile. Despite promising antitumor activity, the mechanism of cytotoxicity and specific cellular target of CbA remain unknown. Here, we develop an optimized synthetic CbA photoaffinity probe (photo-CbA) and use...
Article
Effector CD4⁺ T cells can be classified by the cytokines they secrete, with T helper 1 (Th1) cells generating interferon (IFN)γ and Th17 cells secreting interleukin (IL)-17. Both Th1 and Th17 cells are strongly implicated in the initiation and chronicity of autoimmune diseases such as multiple sclerosis. The endoplasmic reticulum (ER) has been impl...
Article
Full-text available
Kendomycin is a small-molecule natural product that has gained significant attention due to reported cytotoxicity against pathogenic bacteria and fungi as well as a number of cancer cell lines. Despite significant biomedical interest and attempts to reveal its mechanism of action, the cellular target of kendomycin remains disputed. Herein it is sho...
Article
Full-text available
Covering: up to the end of 2019 Diverse natural product small molecules have allowed critical insights into processes that govern eukaryotic cells' ability to secrete cytosolically synthesized secretory proteins into their surroundings or to insert newly synthesized integral membrane proteins into the lipid bilayer of the endoplasmic reticulum. In...
Preprint
Coibamide A (CbA) is a marine natural product with potent antiproliferative activity against human cancer cells and a unique selectivity profile. Despite promising antitumor activity, the mechanism of cytotoxicity and specific cellular target remain unknown. Here, we develop an optimized synthetic CbA photoaffinity probe (photo-CbA) and use it to d...
Article
Full-text available
Physiological nucleosides are used for the synthesis of DNA, RNA, and ATP in the cell and serve as universal mammalian signaling molecules that regulate physiological processes such as vasodilation and platelet aggregation by engaging with cell surface receptors. The same pathways that allow uptake of physiological nucleosides mediate the cellular...
Article
Many functions of eukaryotic cells are compartmentalized within membrane-bound organelles. One or more cis-encoded signals within a polypeptide sequence typically govern protein targeting to and within destination organelles. Perhaps unexpectedly, organelle targeting does not occur with high specificity, but instead is characterized by considerable...
Preprint
Full-text available
Intracellular pH is a potent modulator of neuronal functions. By catalyzing (de)hydration of CO 2 , intracellular carbonic anhydrase (CA i ) isoforms CAII and CAVII contribute to neuronal pH buffering and dynamics. The presence of two highly active isoforms suggests that they form spatially distinct CA i pools enabling subcellular modulation of pH....
Article
Full-text available
Ipomoeassin F is a potent natural cytotoxin that inhibits growth of many tumor cell lines with single-digit nanomolar potency. However, its biological and pharmacological properties have remained largely unexplored. Building upon our earlier achievements in total synthesis and medicinal chemistry, we used chemical proteomics to identify Sec61α (pro...
Article
Full-text available
Rapamycin and FK506 are macrocyclic natural products with an extraordinary mode of action, in which they form binary complexes with FK506-binding protein (FKBP) through a shared FKBP-binding domain before forming ternary complexes with their respective targets, mechanistic target of rapamycin (mTOR) and calcineurin, respectively. Inspired by this,...
Preprint
The ipomoeassin family of natural resin glycosides is underexplored chemical space with potent antitumor activity revealed in the NCI-60 cell lines screen; however, its mode of action has so far remained unexplored. In this manuscript, we report our chemical proteomics and subsequent biology studies that transform our collective knowledge of the ip...
Poster
One of the first cellular response to a variety of stress inducers is the inhibition of cap-dependent protein synthesis. This also occurs as a first defense mechanism against viruses, which must evolve counter-defense strategies to overcome the attempt of the cell to block viral protein production. We discovered that a mammalian virus, vesicular st...
Article
Full-text available
Many actin cytoskeleton-regulating proteins control dendritic spine morphology and density, which are cellular features often altered in autism spectrum disorder (ASD). Recent studies using animal models show that autism-related behavior can be rescued by either manipulating actin regulators or by reversing dendritic spine density or morphology. Ba...
Article
Full-text available
Mycolactone is a bacteria-derived macrolide that blocks the biogenesis of a large array of secretory and integral transmembrane proteins (TMP) through potent inhibition of the Sec61 translocon. Here, we used quantitative proteomics to delineate the direct and indirect effects of mycolactone-mediated Sec61 blockade in living cells. In T lymphocytes,...
Article
The human equilibrative nucleoside transporter-1 (hENT1) is an important for the entry of anti-cancer and anti-viral nucleoside analog therapeutics into the cell, and thus for their efficacy. Understanding of hENT1 structure–function relationship could assist with development of nucleoside analogs with better cellular uptake properties. However, st...
Article
Full-text available
Fragment-based ligand design and covalent targeting of noncatalytic cysteines have been employed to develop potent and selective kinase inhibitors. Here, we combine these approaches, starting with a panel of low-molecular-weight, heteroaryl-susbstituted cyanoacrylamides, which we have previously shown to form reversible covalent bonds with cysteine...
Article
Small molecules that perturb protein homeostasis are used as cancer therapeutics and as antibiotics to treat bacterial infections. In a recent issue of Cell, Kannan and colleagues describe an intriguing mechanism that enables ribosome-targeted macrolides to selectively remodel the bacterial proteome. This finding suggests the exciting possibility o...
Article
Cell locomotion and endocytosis are powered by the rapid polymerization and turnover of branched actin filament networks nucleated by Arp2/3 complex. Although a large number of cellular factors have been identified that stimulate Arp2/3 complex-mediated actin nucleation, only a small number of studies so far have addressed which factors promote act...
Chapter
Twinfilin family actin monomer-binding proteins are conserved in evolution from yeasts to mammals. They bind ADP-actin monomers with high affinity and prevent the assembly of actin monomers into filament ends. In addition to monomeric actin, twinfilins also bind and cap actin filament barbed ends, and interact direcdy with heterodimeric capping pro...
Article
Full-text available
The actin cytoskeleton plays a fundamental role in various motile and morphogenetic processes involving membrane dynamics. We show that actin-binding proteins MIM (missing-in-metastasis) and IRSp53 directly bind PI(4,5)P(2)-rich membranes and deform them into tubular structures. This activity resides in the N-terminal IRSp53/MIM domain (IMD) of the...
Article
Full-text available
Dynamic reorganization of the actin cytoskeleton is essential for motile and morphological processes in all eukaryotic cells. One highly conserved protein that regulates actin dynamics is twinfilin, which both sequesters actin monomers and caps actin filament barbed ends. Twinfilin is composed of two ADF/cofilin-like domains, Twf-N and Twf-C. Here,...
Article
Coactosin is a small (MW approximately 15 kDa) evolutionarily conserved actin filament binding protein. It displays remote sequence homology to ADF/cofilin proteins and to the ADF-H domains of twinfilin and Abp1/drebrin. However, biochemical analyses have demonstrated that coactosin has a very different role in actin dynamics from the ones of ADF/c...
Article
Full-text available
Twinfilin and capping protein (CP) are highly conserved actin-binding proteins that regulate cytoskeletal dynamics in organisms from yeast to mammals. Twinfilin binds actin monomer, while CP binds the barbed end of the actin filament. Remarkably, twinfilin and CP also bind directly to each other, but the mechanism and role of this interaction in ac...
Article
The actin cytoskeleton is a vital component of several key cellular and developmental processes in eukaryotes. Many proteins that interact with filamentous and/or monomeric actin regulate the structure and dynamics of the actin cytoskeleton. Actin-filament-binding proteins control the nucleation, assembly, disassembly and crosslinking of actin fila...
Article
Full-text available
Twinfilin is an evolutionarily conserved actin monomer-binding protein that regulates cytoskeletal dynamics in organisms from yeast to mammals. It is composed of two actin-depolymerization factor homology (ADF-H) domains that show approximately 20% sequence identity to ADF/cofilin proteins. In contrast to ADF/cofilins, which bind both G-actin and F...
Article
Full-text available
Twinfilin is a ubiquitous and abundant actin monomer-binding protein that is composed of two ADF-H domains. To elucidate the role of twinfilin in actin dynamics, we examined the interactions of mouse twinfilin and its isolated ADF-H domains with G-actin. Wild-type twinfilin binds ADP-G-actin with higher affinity (K(D) = 0.05 microM) than ATP-G-acti...
Article
Cofilin/ADF is a ubiquitous actin-binding protein that is important for rapid actin dynamics in vivo. The long a-helix (helix 3 in yeast cofilin) forms the most highly conserved region in cofilin/ADF proteins, and residues in the NH2-terminal half of this a-helix have been shown to be essential for actin binding in cofilin/ADF. Recent studies also...
Article
The actin cytoskeleton is required, in all eukaryotic organisms, for several key cellular functions such as cell motility, cytokinesis, and endocytosis. In cells, actin exists either in a monomeric state (G-actin) or in a filamentous form (F-actin). F-actin is the functional form, which can assemble into various structures and produce direct pushin...

Network

Cited By

Projects

Projects (2)
Archived project
To dissect the structural and biochemical understandings of role of Siepin in lipid storage and sorting.
Project
Structural insights into protein translocation machinery