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Marlen Dierich, Alessandro Altoè, Julia Koppelmann, Saskia Evers, Vijay Renigunta, Martin K Schäfer, Ronald Naumann, Sarah Verhulst, Dominik Oliver, Michael G Leitner
Optimized Tuning of Auditory Inner Hair Cells to Encode Complex Sound through Synergistic Activity of Six Independent K+ Current Entities.
Cell Rep, 32(1) 107869-107869 (2020)
PubMed Source   

Auditory inner hair cells (IHCs) convert sound vibrations into receptor potentials that drive synaptic transmission. For the precise encoding of sound qualities, receptor potentials are shaped by K+ conductances tuning the properties of the IHC membrane. Using patch-clamp and computational modeling, we unravel this membrane specialization showing that IHCs express an exclusive repertoire of six voltage-dependent K+ conductances mediated by Kv1.8, Kv7.4, Kv11.1, Kv12.1, and BKCa channels. All channels are active at rest but are triggered differentially during sound stimulation. This enables non-saturating tuning over a far larger potential range than in IHCs expressing fewer current entities. Each conductance contributes to optimizing responses, but the combined activity of all channels synergistically improves phase locking and the dynamic range of intensities that IHCs can encode. Conversely, hypothetical simpler IHCs appear limited to encode only certain aspects (frequency or intensity). The exclusive channel repertoire of IHCs thus constitutes an evolutionary adaptation to encode complex sound through multifaceted receptor potentials.
@article{Dierich7705,
author={Marlen Dierich, Alessandro Altoè, Julia Koppelmann, Saskia Evers, Vijay Renigunta, Martin K Schäfer, Ronald Naumann, Sarah Verhulst, Dominik Oliver, Michael G Leitner},
title={Optimized Tuning of Auditory Inner Hair Cells to Encode Complex Sound through Synergistic Activity of Six Independent K+ Current Entities.},
journal ={Cell reports},
volume={32},
issue ={1},
pages={107869--107869},
year=2020
}

Thomas E. Gorochowski, Sabine Hauert, Jan-Ulrich Kreft, Lucia Marucci, Namid R. Stillman, T-Y Dora Tang, Lucia Bandiera, Vittorio Bartoli, Daniel O.R. Dixon, Alex J.H. Fedorec, Harold Fellermann, Alexander G. Fletcher, Tim Foster, Luca Giuggioli, Antoni Matyjaskiewicz, Scott McCormick, Sandra Montes Olivas, Jonathan Naylor, Ana Rubio Denniss, Daniel Ward
Toward Engineering Biosystems With Emergent Collective Functions.
Front Bioeng Biotechnol, 8 Art. No. doi: 10.3389/fbioe.2020.00705 (2020)
Source   

Many complex behaviors in biological systems emerge from large populations of interacting molecules or cells, generating functions that go beyond the capabilities of the individual parts. Such collective phenomena are of great interest to bioengineers due to their robustness and scalability. However, engineering emergent collective functions is difficult because they arise as a consequence of complex multi-level feedback, which often spans many length-scales. Here, we present a perspective on how some of these challenges could be overcome by using multi-agent modeling as a design framework within synthetic biology. Using case studies covering the construction of synthetic ecologies to biological computation and synthetic cellularity, we show how multi-agent modeling can capture the core features of complex multi-scale systems and provide novel insights into the underlying mechanisms which guide emergent functionalities across scales. The ability to unravel design rules underpinning these behaviors offers a means to take synthetic biology beyond single molecules or cells and toward the creation of systems with functions that can only emerge from collectives at multiple scales.
@article{Gorochowski7704,
author={Thomas E. Gorochowski, Sabine Hauert, Jan-Ulrich Kreft, Lucia Marucci, Namid R. Stillman, T-Y Dora Tang, Lucia Bandiera, Vittorio Bartoli, Daniel O.R. Dixon, Alex J.H. Fedorec, Harold Fellermann, Alexander G. Fletcher, Tim Foster, Luca Giuggioli, Antoni Matyjaskiewicz, Scott McCormick, Sandra Montes Olivas, Jonathan Naylor, Ana Rubio Denniss, Daniel Ward},
title={Toward Engineering Biosystems With Emergent Collective Functions.},
journal ={Frontiers in Bioengineering and Biotechnology},
volume={8},
pages={null--null},
year=2020
}

Katharina Holzhüter, Eric R Geertsma
Functional (un)cooperativity in elevator transport proteins.
Biochem Soc Trans, Art. No. doi: 10.1042/BST20190970 (2020)
PubMed Source   

The activity of enzymes is subject to regulation at multiple levels. Cooperativity, the interconnected behavior of active sites within a protein complex, directly affects protein activity. Cooperativity is a mode of regulation that requires neither extrinsic factors nor protein modifications. Instead, it allows enzymes themselves to modulate reaction rates. Cooperativity is an important regulatory mechanism in soluble proteins, but also examples of cooperative membrane proteins have been described. In this review, we summarize the current knowledge on interprotomer cooperativity in elevator-type proteins, a class of membrane transporters characterized by large rigid-body movements perpendicular to the membrane, and highlight well-studied examples and experimental approaches.
@article{Holzhüter7703,
author={Katharina Holzhüter, Eric R Geertsma},
title={Functional (un)cooperativity in elevator transport proteins.},
journal ={Biochemical Society transactions},
volume={},
pages={1--1},
year=2020
}

Verena Henrichs, Lenka Grycova, Cyril Barinka, Zuzana Nahacka, Jiri Neuzil, Stefan Diez, Jakub Rohlena, Marcus Braun, Zdenek Lansky
Mitochondria-adaptor TRAK1 promotes kinesin-1 driven transport in crowded environments.
Nat Commun, 11(1) Art. No. 3123 (2020)
PubMed Source   

Intracellular trafficking of organelles, driven by kinesin-1 stepping along microtubules, underpins essential cellular processes. In absence of other proteins on the microtubule surface, kinesin-1 performs micron-long runs. Under crowding conditions, however, kinesin-1 motility is drastically impeded. It is thus unclear how kinesin-1 acts as an efficient transporter in intracellular environments. Here, we demonstrate that TRAK1 (Milton), an adaptor protein essential for mitochondrial trafficking, activates kinesin-1 and increases robustness of kinesin-1 stepping on crowded microtubule surfaces. Interaction with TRAK1 i) facilitates kinesin-1 navigation around obstacles, ii) increases the probability of kinesin-1 passing through cohesive islands of tau and iii) increases the run length of kinesin-1 in cell lysate. We explain the enhanced motility by the observed direct interaction of TRAK1 with microtubules, providing an additional anchor for the kinesin-1-TRAK1 complex. Furthermore, TRAK1 enables mitochondrial transport in vitro. We propose adaptor-mediated tethering as a mechanism regulating kinesin-1 motility in various cellular environments.
@article{Henrichs7701,
author={Verena Henrichs, Lenka Grycova, Cyril Barinka, Zuzana Nahacka, Jiri Neuzil, Stefan Diez, Jakub Rohlena, Marcus Braun, Zdenek Lansky},
title={Mitochondria-adaptor TRAK1 promotes kinesin-1 driven transport in crowded environments.},
journal ={Nature communications},
volume={11},
issue ={1},
pages={null--null},
year=2020
}

Isaac A Klein, Ann Boija, Lena K Afeyan, Susana Wilson Hawken, Mengyang Fan, Alessandra Dall'Agnese, Ozgur Oksuz, Jonathan E Henninger, Krishna Shrinivas, Benjamin R Sabari, Ido Sagi, Victoria E Clark, Jesse M Platt, Mrityunjoy Kar, Patrick M McCall, Alicia V Zamudio, John C Manteiga, Eliot L Coffey, Charles H Li, Nancy M Hannett, Yang Eric Guo, Tim-Michael Decker, Tong Ihn Lee, Tinghu Zhang, Jing-Ke Weng, Dylan J Taatjes, Arup Chakraborty, Phillip A Sharp, Young Tae Chang, Anthony Hyman, Nathanael S Gray, Richard A Young
Partitioning of cancer therapeutics in nuclear condensates.
Science, 368(6497) 1386-1392 (2020)
PubMed Source   

The nucleus contains diverse phase-separated condensates that compartmentalize and concentrate biomolecules with distinct physicochemical properties. Here, we investigated whether condensates concentrate small-molecule cancer therapeutics such that their pharmacodynamic properties are altered. We found that antineoplastic drugs become concentrated in specific protein condensates in vitro and that this occurs through physicochemical properties independent of the drug target. This behavior was also observed in tumor cells, where drug partitioning influenced drug activity. Altering the properties of the condensate was found to affect the concentration and activity of drugs. These results suggest that selective partitioning and concentration of small molecules within condensates contributes to drug pharmacodynamics and that further understanding of this phenomenon may facilitate advances in disease therapy.
@article{Klein7699,
author={Isaac A Klein, Ann Boija, Lena K Afeyan, Susana Wilson Hawken, Mengyang Fan, Alessandra Dall'Agnese, Ozgur Oksuz, Jonathan E Henninger, Krishna Shrinivas, Benjamin R Sabari, Ido Sagi, Victoria E Clark, Jesse M Platt, Mrityunjoy Kar, Patrick M McCall, Alicia V Zamudio, John C Manteiga, Eliot L Coffey, Charles H Li, Nancy M Hannett, Yang Eric Guo, Tim-Michael Decker, Tong Ihn Lee, Tinghu Zhang, Jing-Ke Weng, Dylan J Taatjes, Arup Chakraborty, Phillip A Sharp, Young Tae Chang, Anthony Hyman, Nathanael S Gray, Richard A Young},
title={Partitioning of cancer therapeutics in nuclear condensates.},
journal ={Science (New York, N.Y.)},
volume={368},
issue ={6497},
pages={1386--1392},
year=2020
}

Michael Heide, Christiane Haffner, Ayako Y Murayama, Yoko Kurotaki, Haruka Shinohara, Hideyuki Okano, Erika Sasaki, Wieland Huttner
Human-specific ARHGAP11B increases size and folding of primate neocortex in the fetal marmoset.
Science, Art. No. doi: 10.1126/science.abb2401 (2020)
PubMed Source   

The neocortex has expanded during mammalian evolution. Overexpression studies in developing mouse and ferret neocortex have implicated the human-specific gene ARHGAP11B in neocortical expansion, but the relevance for primate evolution has been unclear. Here, we provide functional evidence that ARHGAP11B causes expansion of the primate neocortex. ARHGAP11B expressed in fetal neocortex of the common marmoset under control of the gene's own, human, promoter increased numbers of basal radial glia progenitors in the marmoset outer subventricular zone, increased numbers of upper-layer neurons, enlarged the neocortex, and induced its folding. Thus, the human-specific ARHGAP11B drives changes in development in the non-human primate marmoset that reflect the changes in evolution that characterize human neocortical development.
@article{Heide7693,
author={Michael Heide, Christiane Haffner, Ayako Y Murayama, Yoko Kurotaki, Haruka Shinohara, Hideyuki Okano, Erika Sasaki, Wieland Huttner},
title={Human-specific ARHGAP11B increases size and folding of primate neocortex in the fetal marmoset.},
journal ={Science (New York, N.Y.)},
volume={},
pages={1--1},
year=2020
}

Deepthi Ashokkumar, Qinyu Zhang, Christian Much, Anita S. Bledau, Ronald Naumann, Dimitra Alexopoulou, Andreas Dahl, Neha Goveas, Jun Fu, Konstantinos Anastassiadis, A F Stewart, Andrea Kranz
MLL4 is required after implantation, whereas MLL3 becomes essential during late gestation.
Development, 147(12) Art. No. dev.186999 (2020)
PubMed Source   

Methylation of histone 3 lysine 4 (H3K4) is a major epigenetic system associated with gene expression. In mammals there are six H3K4 methyltransferases related to yeast Set1 and fly Trithorax, including two orthologs of fly Trithorax-related: MLL3 and MLL4. Exome sequencing has documented high frequencies of MLL3 and MLL4 mutations in many types of human cancer. Despite this emerging importance, the requirements of these paralogs in mammalian development have only been incompletely reported. Here, we examined the null phenotypes to establish that MLL3 is first required for lung maturation, whereas MLL4 is first required for migration of the anterior visceral endoderm that initiates gastrulation in the mouse. This collective cell migration is preceded by a columnar-to-squamous transition in visceral endoderm cells that depends on MLL4. Furthermore, Mll4 mutants display incompletely penetrant, sex-distorted, embryonic haploinsufficiency and adult heterozygous mutants show aspects of Kabuki syndrome, indicating that MLL4 action, unlike MLL3, is dosage dependent. The highly specific and discordant functions of these paralogs in mouse development argues against their action as general enhancer factors.
@article{Ashokkumar7678,
author={Deepthi Ashokkumar, Qinyu Zhang, Christian Much, Anita S. Bledau, Ronald Naumann, Dimitra Alexopoulou, Andreas Dahl, Neha Goveas, Jun Fu, Konstantinos Anastassiadis, A F Stewart, Andrea Kranz},
title={MLL4 is required after implantation, whereas MLL3 becomes essential during late gestation.},
journal ={Development (Cambridge, England)},
volume={147},
issue ={12},
pages={null--null},
year=2020
}

Elisabeth Nüske, Guendalina Marini, Doris Richter, Weihua Leng, Aliona Bogdanova, Titus Franzmann, Gaia Pigino, Simon Alberti
Filament formation by the translation factor eIF2B regulates protein synthesis in starved cells.
Biol Open, Art. No. bio.046391 (2020)
PubMed Source   

Cells exposed to starvation have to adjust their metabolism to conserve energy and protect themselves. Protein synthesis is one of the major energy-consuming processes and as such has to be tightly controlled. Many mechanistic details about how starved cells regulate the process of protein synthesis are still unknown. Here, we report that the essential translation initiation factor eIF2B forms filaments in starved budding yeast cells. We demonstrate that filamentation is triggered by starvation-induced acidification of the cytosol, which is caused by an influx of protons from the extracellular environment. We show that filament assembly by eIF2B is necessary for rapid and efficient downregulation of translation. Importantly, this mechanism does not require the kinase Gcn2. Furthermore, analysis of site-specific variants of eIF2B suggests that eIF2B assembly results in enzymatically inactive filaments that promote stress survival and fast recovery of cells from starvation. We propose that translation regulation through filament formation is an efficient mechanism that allows yeast cells to adapt to fluctuating environments.
@article{Nüske7700,
author={Elisabeth Nüske, Guendalina Marini, Doris Richter, Weihua Leng, Aliona Bogdanova, Titus Franzmann, Gaia Pigino, Simon Alberti},
title={Filament formation by the translation factor eIF2B regulates protein synthesis in starved cells.},
journal ={Biology open},
volume={},
pages={null--null},
year=2020
}

Marcus Braun, Stefan Diez, Zdenek Lansky
Cytoskeletal organization through multivalent interactions.
J Cell Sci, 133(12) Art. No. jcs234393 (2020)
PubMed Source   

The cytoskeleton consists of polymeric protein filaments with periodic lattices displaying identical binding sites, which establish a multivalent platform for the binding of a plethora of filament-associated ligand proteins. Multivalent ligand proteins can tether themselves to the filaments through one of their binding sites, resulting in an enhanced reaction kinetics for the remaining binding sites. In this Opinion, we discuss a number of cytoskeletal phenomena underpinned by such multivalent interactions, namely (1) generation of entropic forces by filament crosslinkers, (2) processivity of molecular motors, (3) spatial sorting of proteins, and (4) concentration-dependent unbinding of filament-associated proteins. These examples highlight that cytoskeletal filaments constitute the basis for the formation of microenvironments, which cytoskeletal ligand proteins can associate with and, once engaged, can act within at altered reaction kinetics. We thus argue that multivalency is one of the properties crucial for the functionality of the cytoskeleton.
@article{Braun7702,
author={Marcus Braun, Stefan Diez, Zdenek Lansky},
title={Cytoskeletal organization through multivalent interactions.},
journal ={Journal of cell science},
volume={133},
issue ={12},
pages={1--1},
year=2020
}

Katarina Liedtke, Christina Alter, Anne Günther, Nadine Hövelmeyer, Robert Klopfleisch, Ronald Naumann, F Thomas Wunderlich, Jan Buer, Astrid M Westendorf, Wiebke Hansen
Endogenous CD83 Expression in CD4+ Conventional T Cells Controls Inflammatory Immune Responses.
J Immunol, 204(12) 3217-3226 (2020)
PubMed Source   

The glycoprotein CD83 is known to be expressed by different immune cells including activated CD4+Foxp3+ regulatory T cells (Tregs) and CD4+Foxp3- conventional T cells. However, the physiological function of endogenous CD83 in CD4+ T cell subsets is still unclear. In this study, we have generated a new CD83flox mouse line on BALB/c background, allowing for specific ablation of CD83 in T cells upon breeding with CD4-cre mice. Tregs from CD83flox/flox/CD4-cretg/wt mice had similar suppressive activity as Tregs from CD83flox/flox/CD4-crewt/wt wild-type littermates, suggesting that endogenous CD83 expression is dispensable for the inhibitory capacity of Tregs. However, CD83-deficient CD4+ conventional T cells showed elevated proliferation and IFN-γ secretion as well as an enhanced capacity to differentiate into Th1 cells and Th17 cells upon stimulation in vitro. T cell-specific ablation of CD83 expression resulted in aggravated contact hypersensitivity reaction accompanied by enhanced CD4+ T cell activation. Moreover, adoptive transfer of CD4+CD45RBhigh T cells from CD83flox/flox/CD4-cretg/wt mice into Rag2-deficient mice elicited more severe colitis associated with increased serum concentrations of IL-12 and elevated CD40 expression on CD11c+ dendritic cells (DCs). Strikingly, DCs from BALB/c mice cocultured with CD83-deficient CD4+ conventional T cells showed enhanced CD40 expression and IL-12 secretion compared with DCs cocultured with CD4+ conventional T cells from CD83flox/flox/CD4-crewt/wt wild-type mice. In summary, these results indicate that endogenous CD83 expression in CD4+ conventional T cells plays a crucial role in controlling CD4+ T cell responses, at least in part, by regulating the activity of CD11c+ DCs.
@article{Liedtke7659,
author={Katarina Liedtke, Christina Alter, Anne Günther, Nadine Hövelmeyer, Robert Klopfleisch, Ronald Naumann, F Thomas Wunderlich, Jan Buer, Astrid M Westendorf, Wiebke Hansen},
title={Endogenous CD83 Expression in CD4+ Conventional T Cells Controls Inflammatory Immune Responses.},
journal ={Journal of immunology (Baltimore, Md. : 1950)},
volume={204},
issue ={12},
pages={3217--3226},
year=2020
}