Insights into Membrane Curvature Sensing and Membrane Remodeling by Intrinsically Disordered Proteins and Protein Regions

Abstract

Cellular membranes are highly dynamic in shape. They can rapidly and precisely regulate their shape to perform various cellular functions. The protein’s ability to sense membrane curvature is essential in various biological events such as cell signaling and membrane trafficking. As they are bound, these curvature-sensing proteins may also change the local membrane shape by one or more curvature driving mechanisms. Established curvature-sensing/driving mechanisms rely on proteins with specific structural features such as amphipathic helices and intrinsically curved shapes. However, the recent discovery and characterization of many proteins have shattered the protein structure–function paradigm, believing that the protein functions require a unique structural feature. Typically, such structure-independent functions are carried either entirely by intrinsically disordered proteins or hybrid proteins containing disordered regions and structured domains. It is becoming more apparent that disordered proteins and regions can be potent sensors/inducers of membrane curvatures. In this article, we outline the basic features of disordered proteins and regions, the motifs in such proteins that encode the function, membrane remodeling by disordered proteins and regions, and assays that may be employed to investigate curvature sensing and generation by ordered/disordered proteins. Graphical Abstract

Digital nanoreactors for control over absolute stoichiometry and spatiotemporal behavior of receptors within lipid bilayers

“…Experiments to verify these aspects of DOL will be required to delineate the conditions under which DOL can be modeled as simple nanoreactors in which the membrane is homogeneous and its biophysical properties (e.g., receptor diffusion constant) are independent of DOL size. For proteins whose oligomerization behavior depends on membrane curvature, 85,86 the assumption of DOL size-independent behavior will likely fail, making modeling more challenging. On the positive side, wherever membrane biophysics does turn out to be DOL size-dependent, development of a series of DOL having a range of diameters could enable new opportunities—e.g., protein sensors of membrane curvature could be studied and engineered.…”

Enhanced sampling for lipid-protein interactions during membrane dynamics

“…Recently, new efforts have been made to improve computational modeling of intrinsically disordered proteins (Thomasen et al, 2022;Klein et al, 2021;Tran and Kitao, 2020). Several reviews have also been dedicated to the role of intrinsic disorder during lipid-protein interactions highlighting the effects on membrane curvature (Has, Sivadas and Das, 2022;Cornish et al, 2020;Fakhree, Blum and Claessens, 2019;Snead and Stachowiak, 2018). Intrinsic disorder presents itself as an additional complexity to the already difficult problem of lipid-protein interactions during biological events that require large configurational and conformational changes.…”

Membrane Remodeling Due to a Mixture of Multiple Types of Curvature Proteins

“…BAR domain class of proteins are the quintessential curvature inducing scaffold proteins and are ubiquitously present in the endocytic recycling pathways and play a crucial role in vesicular transport processes in the cell. ,− BAR family of proteins have a wide range of curvatures with proteins such as F-Bar and N-BAR exhibiting positive curvatures ,, and proteins such as I-BAR exhibiting negative curvature . When these proteins bind to the membrane surface, they impose their local curvature on the membrane and also work in concert with each other at longer length scales to induce nonlocal curvatures on the membrane. − Though the subcellular processes of vesicular transports is mediated by multiple curvature proteins interacting in concert with each other, this aspect has not been studied very much in reconstitution experiments. − Also, lately role of flexible intrinsically disordered regions in scaffolding proteins has been shown to be important, − which highlights the importance of considering the effective curvature of the scaffold protein as a distribution rather than having one fixed curvature value. Even the quintessential “scaffold” proteins such as BAR domain proteins can have extremely anisotropic shapes and a range of interaction strength with the membrane that significantly affects the sorting of proteins on the membrane surface .…”