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Mechanical force can enhance c-Src kinase activity by impairing autoinhibition.

Abstract (Expand)

Cellular mechanosensing is pivotal for virtually all biological processes, and many molecular mechano-sensors and their way of function are being uncovered. In this work, we suggest that c-Src kinase … acts as a direct mechano-sensor. c-Src is responsible for, among others, cell proliferation, and shows increased activity in stretched cells. In its native state, c-Src has little basal activity, because its kinase domain binds to an SH2 and SH3 domain. However, it is known that c-Src can bind to p130Cas, through which force can be transmitted to the membrane. Using molecular dynamics simulations, we show that force acting between the membrane-bound N-terminus of the SH3 domain and p130Cas induces partial SH3 unfolding, thereby impeding rebinding of the kinase domain onto SH2/SH3 and effectively enhancing kinase activity. Forces involved in this process are slightly lower or similar to the forces required to pull out c-Src from the membrane through the myristoyl linker, and key interactions involved in this anchoring are salt bridges between negative lipids and nearby basic residues in c-Src. Thus, c-Src appears to be a candidate for an intriguing mechanosensing mechanism of impaired kinase inhibition, which can be potentially tuned by membrane composition and other environmental factors.

Authors: Csaba Daday, Svenja de Buhr, Davide Mercadante, Frauke Gräter

Date Published: 2nd Feb 2022

Publication Type: Journal

The binding of heparin to spike glycoprotein inhibits SARS-CoV-2 infection by three mechanisms

Abstract

Not specified

Authors: Giulia Paiardi, Stefan Richter, Pasqua Oreste, Chiara Urbinati, Marco Rusnati, Rebecca C. Wade

Date Published: 1st Feb 2022

Publication Type: Journal

Analytic models of the spectral properties of gravitational waves from neutron star merger remnants

Abstract

Not specified

Authors: Theodoros Soultanis, Andreas Bauswein, Nikolaos Stergioulas

Date Published: 1st Feb 2022

Publication Type: Journal

Type Iax supernovae from deflagrations in Chandrasekhar mass white dwarfs

Abstract

Not specified

Authors: F. Lach, F. P. Callan, D. Bubeck, F. K. Röpke, S. A. Sim, M. Schrauth, S. T. Ohlmann, M. Kromer

Date Published: 1st Feb 2022

Publication Type: Journal

Investigating the relationship between tree distance and model distance

Abstract

Not specified

Editor:

Date Published: 1st Feb 2022

Publication Type: Master's Thesis

Computational Models for Clinical Applications in Personalized Medicine-Guidelines and Recommendations for Data Integration and Model Validation.

Abstract (Expand)

The future development of personalized medicine depends on a vast exchange of data from different sources, as well as harmonized integrative analysis of large-scale clinical health and sample data. … Computational-modelling approaches play a key role in the analysis of the underlying molecular processes and pathways that characterize human biology, but they also lead to a more profound understanding of the mechanisms and factors that drive diseases; hence, they allow personalized treatment strategies that are guided by central clinical questions. However, despite the growing popularity of computational-modelling approaches in different stakeholder communities, there are still many hurdles to overcome for their clinical routine implementation in the future. Especially the integration of heterogeneous data from multiple sources and types are challenging tasks that require clear guidelines that also have to comply with high ethical and legal standards. Here, we discuss the most relevant computational models for personalized medicine in detail that can be considered as best-practice guidelines for application in clinical care. We define specific challenges and provide applicable guidelines and recommendations for study design, data acquisition, and operation as well as for model validation and clinical translation and other research areas.

Authors: C. B. Collin, T. Gebhardt, M. Golebiewski, T. Karaderi, M. Hillemanns, F. M. Khan, A. Salehzadeh-Yazdi, M. Kirschner, S. Krobitsch, C. o. n. s. o. r. t. i. u. m. Eu-Stands Pm, L. Kuepfer

Date Published: 26th Jan 2022

Publication Type: Journal

Phosphorylation tunes elongation propensity and cohesiveness of INCENP's intrinsically disordered region.

Abstract (Expand)

The inner centromere protein, INCENP, is crucial for correct chromosome segregation during mitosis. It connects the kinase Aurora B to the inner centromere allowing this kinase to dynamically access … its kinetochore targets. However, the function of its central, 440-residue long intrinsically disordered region (IDR) and its multiple phosphorylation sites is unclear. Here, we determined the conformational ensemble of INCENP's IDR, systematically varying the level of phosphorylation, using all-atom and coarse-grain molecular dynamics simulations. Our simulations show that phosphorylation expands INCENP's IDR, both locally and globally, mainly by increasing its overall net charge. The disordered region undergoes critical globule-to-coil conformational transitions and the transition temperature non-monotonically depends on the degree of phosphorylation, with a mildly phosphorylated case of neutral net charge featuring the highest collapse propensity. The IDR transitions from a multitude of globular states, accompanied by several specific internal contacts that reduce INCENP length by loop formation, to weakly interacting and highly extended coiled conformations. Phosphorylation critically shifts the population between these two regimes. It thereby influences cohesiveness and phase behavior of INCENP IDR assemblies, a feature presumably relevant for INCENP's function in the chromosomal passenger complex. Overall, we propose the disordered region of INCENP to act as a phosphorylation-regulated and length-variable component, within the previously defined "dog-leash" model, that thereby regulates how Aurora B reaches its targets for proper chromosome segregation.

Authors: Isabel M Martin, Camilo Aponte-Santamaría, Lisa Schmidt, Marius Hedtfeld, Adel Iusupov, Andrea Musacchio, Frauke Gräter

Date Published: 15th Jan 2022

Publication Type: Journal

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