2024
Research News
USTC Realizes Quantitative Ensemble Interpretation of Membrane Paramagnetic Relaxation Enhancement for Intrinsically Disordered Proteins
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Intrinsically disordered proteins (IDPs) are widely found in the proteomes of eukaryotes and play key roles in life processes such as transcription of genetic information and signaling. IDPs become the basis of the “Disorder–function paradigm” of proteins. Over the last two decades, the role of IDPs has been actively studied. How to characterize the highly flexible and heterogeneous conformations of IDPs at high resolution remains a key issue.
More than 15% of IDP molecules are membrane-bound in cells, and their internal dynamics and overall (translational and rotational) motions within the phospholipid bilayers are closely related to their physicochemical properties and biological functions. However, these dynamic processes are difficult to be captured and quantitatively characterized by conventional structural analysis methods.
A research group led by Prof. LONG Dong from the University of Science and Technology of China (USTC) of the Chinese Academy of Sciences has developed an IDP spectroscopy method based on the membrane paramagnetic relaxation enhancement (mPRE) technique, which has achieved high-precision modeling of the internal conformations, orientations, and immersion depths of IDPs. The study was published in Journal of the American Chemical Society.
The researchers explored in detail the flexibility and mobility of the spin probe molecules within the membrane for accurate interpretation of the mPRE spectral data, and proposed a a weighted three-dimensional (3D) grid model based on all-atom simulations for quantitatively portraying the effect of the spin probe dynamics on the membrane paramagnetic relaxation enhancement rate.
Besides, the researchers developed an algorithm which is detailed in the Supporting Information (SI) for optimizing the global and internal degrees of the freedom of membrane-bound IDPs via superposition of z-coordinates only. The high computational efficiency of the 3D grid model made the algorithm tailored for the mPRE data analysis, constructing an all-atom ensemble model of IDP in an implicit membrane environment.
CD3ε is a component of the T-cell receptor complex responsible for T-cell antigen recognition. The CD3ε cytoplasmic domain (CD3εCD) contains immunoreceptor tyrosine-based activation motifs (ITAMs), and it forms a fuzzy complex with lipid bilayers in an intrinsically disordered state, and regulates the signaling activity of the fuzzy complex by utilizing dynamic membrane shielding of key tyrosine sites.
The researchers resolved the ensemble based on molecular dynamics of CD3εCD in lipid bilayers by applying an all-atom ensemble model solution of IDP in an implicit membrane environment. The ensemble from mPRE experimental parameters mapped the dynamic distribution of CD3εCD in different regions of the membrane at the atomic level and revealed key differences in the membrane interactions of different tyrosine sites on ITAM, providing a new mechanistic explanation for the monophosphorylation pattern of ITAM.
The mPRE spectroscopic analysis method developed in this work is expected to facilitate atomic resolution studies of various functional membrane IDPs.
The Modelling of membrane-associated IDP ensemble based on mPRE rate (Image by USTC)
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