Biology subjects

Sorgenfrei, F. A.

Publications and source records attributed to Sorgenfrei, F. A..

3 recordsLinked to original sources

bioRxiv2021

The dynamic properties of a nuclear coactivator binding domain are evolutionarily conserved

Evolution of proteins is constrained by their structure and function. While there is a consensus that the plasticity of intrinsically disordered proteins relaxes the structural constraints on evolution there is a paucity of data on the molecular details of these processes. The Nuclear co-activator binding domain (NCBD) from CREB-binding protein is a protein-protein interaction domain, which contains a hydrophobic core but is not behaving as a typical globular domain, and has been desribed as molten-globule like. The highly dynamic properties of NCBD makes it an interesting model system for evolutionary structure-function investigation of intrinsically disordered proteins. We have here compared the structure and biophysical properties of an ancient version of NCBD present in a bilaterian animal ancestor living around 600 million years ago with extant human NCBD. Using a combination of NMR spectroscopy, circular dichroism and kinetic methods we show that although NCBD has increased its thermodynamic stability, it has retained its dynamic biophysical properties in the ligand-free state in the evolutionary lineage leading from the last common bilaterian ancestor to humans. Our findings suggest that the dynamic properties of NCBD have been maintained by purifying selection and thus are important for its function, which includes mediating several distinct protein-protein interactions.

biophysics↗

bioRxiv2020

Optimal time frequency analysis for biological data - pyBOAT

Methods for the quantification of rhythmic biological signals have been essential for the discovery of function and design of biological oscillators. Advances in live measurements have allowed recordings of unprecedented resolution revealing a new world of complex heterogeneous oscillations with multiple noisy non-stationary features. However, our understanding of the underlying mechanisms regulating these oscillations has been lagging behind, partially due to the lack of simple tools to reliably quantify these complex non-stationary features. With this challenge in mind, we have developed pyBOAT, a Python-based fully automatic stand-alone software that integrates multiple steps of non-stationary oscillatory time series analysis into an easy-to-use graphical user interface. pyBOAT implements continuous wavelet analysis which is specifically designed to reveal time-dependent features. In this work we illustrate the advantages of our tool by analyzing complex non-stationary time-series profiles. Our approach integrates data-visualization, optimized sinc-filter detrending, amplitude envelope removal and a subsequent continuous-wavelet based time-frequency analysis. Finally, using analytical considerations and numerical simulations we discuss unexpected pitfalls in commonly used smoothing and detrending operations.

systems biology↗

bioRxiv2020

Evolution of an interaction between disordered proteins resulted in increased heterogeneity of the binding transition state

Intrinsically disordered protein (IDP) domains often have multiple binding partners. Little is known regarding molecular changes in the binding mechanism when a new interaction evolves from low to high affinity. Here we compared the degree of native contacts in the transition state of the interaction of two IDP domains, low-affinity ancestral and high-affinity human NCBD and CID. We found that the coupled binding and folding mechanism of the domains is overall similar, but with a higher degree of native hydrophobic contact formation in the transition state of the ancestral complex while more heterogenous transient interactions, including electrostatic, and an increased disorder characterize the human complex. From an evolutionary perspective, adaptation to new binding partners for IDPs may benefit from this ability to exploit multiple alternative transient interactions while retaining the overall pathway.

biophysics↗