Current opinion in structural biology最新文献

Nanodiscs represent a versatile tool for studies of membrane proteins and protein-membrane interactions under native-like conditions. Multiple variations of the Nanodisc platform, as well as new experimental methods, have been recently developed to understand various aspects of structure, dynamics and functional properties of systems involved in signaling, transport, blood coagulation and many other critically important processes. In this mini-review, we focus on some of these exciting recent developments that utilize the Nanodisc platform.

Recent technological advances have deepened our perception of cellular structure. However, most structural data doesn't originate from intact cells, limiting our understanding of cellular processes. Here, we discuss current and future developments that will bring us towards a structural picture of the cell. Electron cryotomography is the standard bearer, with its ability to provide in cellulo snapshots. Single-particle electron microscopy (of purified biomolecules and of complex mixtures) and covalent crosslinking combined with mass spectrometry also have significant roles to play, as do artificial intelligence algorithms in their many guises. To integrate these multiple approaches, data curation and standardisation will be critical – as is the need to expand efforts beyond our current protein-centric view to the other (macro)molecules that sustain life.

Micronuclei (MN) form from missegregated chromatin that recruits its own nuclear envelope during mitotic exit and are a common consequence of chromosomal instability. MN are unstable due to errors in nuclear envelope organization and frequently rupture, leading to loss of compartmentalization, loss of nuclear functions, and major changes in genome stability and gene expression. However, recent work found that, even prior to rupture, nuclear processes can be severely defective in MN, which may contribute to rupture-associated defects and have lasting consequences for chromatin structure and function. In this review we discuss work that highlights nuclear function defects in intact MN, including their mechanisms and consequences, and how biases in chromosome missegregation into MN may affect the penetrance of these defects. Illuminating the nuclear environment of MN demonstrates that MN formation alone has major consequences for both the genome and cell and provides new insight into how nuclear content is regulated.

RNA vaccines have made evident to society what was already known by the scientific community: nucleic acids will be the “drugs of the future.” By modifying the genome, interfering in transcription or translation, and by introducing new catalysts into the cell or by mimicking antibody effects, nucleic acids can generate therapeutic activities that are not accessible by any other therapeutic agents. There are, however, challenges that need to be solved in the next few years to make nucleic acids usable in a wide range of therapeutic scenarios. This review illustrates how simulation methods can help achieve this goal.

Predicting protein interactions in the cellular environment still remains a challenge in the AlphaFold era. Protein interactions, similarly to their structures, sample a continuum from ordered to disordered states, with specific partners in many bound configurations. A multiplicity of binding modes (MBM) enables transition between these states under different cellular conditions. This review focuses on how the cellular environment affects protein interactions, highlighting the molecular mechanisms, biophysical origin, and sequence-based principles of context-dependent, fuzzy interactions. It summarises experimental and computational approaches to address the challenge of interaction heterogeneity and its contribution to a wide range of biological functions. These insights will help in understanding complex cellular processes, involving conversions between protein assembly states, such as from liquid-like droplet state to the amyloid state.

C2H2 zinc-finger (ZF) proteins form the largest family of DNA-binding transcription factors coded by mammalian genomes. In a typical DNA-binding ZF module, there are twelve residues (numbered from −1 to −12) between the last zinc-coordinating cysteine and the first zinc-coordinating histidine. The established C2H2-ZF “recognition code” suggests that residues at positions −1, −4, and −7 recognize the 5′, central, and 3′ bases of a DNA base-pair triplet, respectively. Structural studies have highlighted that additional residues at positions −5 and −8 also play roles in specific DNA recognition. The presence of bulky and either charged or polar residues at these five positions determines specificity for given DNA bases: guanine is recognized by arginine, lysine, or histidine; adenine by asparagine or glutamine; thymine or 5-methylcytosine by glutamate; and unmodified cytosine by aspartate. This review discusses recent structural characterizations of C2H2-ZFs that add to our understanding of the principles underlying the C2H2-ZF recognition code.

Molecular dynamics simulations of cellular membranes have come a long way—from simple model lipid bilayers to multicomponent systems capturing the crowded and complex nature of real cell membranes. In this opinionated minireview, we discuss the current challenge to simulate the dynamics of membranes in their native environment, in situ, with the prospect of reaching the level of whole cells and cell organelles using an integrative modeling framework.

Computational approaches can provide highly detailed insight into the molecular recognition processes that underlie drug binding, the assembly of protein complexes, and the regulation of biological functional processes. Classical simulation methods can bridge a wide range of length- and time-scales typically involved in such processes. Lately, automated learning and artificial intelligence methods have shown the potential to expand the reach of physics-based approaches, ushering in the possibility to model and even design complex protein architectures. The synergy between atomistic simulations and AI methods is an emerging frontier with a huge potential for advances in structural biology. Herein, we explore various examples and frameworks for these approaches, providing select instances and applications that illustrate their impact on fundamental biomolecular problems.

Biological membranes are dynamic heterogeneous materials, and their shape and organization are tightly coupled to the properties of the proteins in and around them. However, the length scales of lipid and protein dynamics are far below the size of membrane-bound organelles, much less an entire cell. Therefore, multiscale modeling approaches are often necessary to build a comprehensive picture of the interplay of these factors, and have provided critical insights into our understanding of membrane dynamics. Here, we review computational methods for studying membrane remodeling, as well as passive and active examples of protein-driven membrane remodeling. As the field advances towards the modeling of key aspects of organelles and whole cells – an increasingly accessible regime of study – we summarize here recent successes and offer comments on future trends.

Many biological membranes host different lipid species in their two leaflets. Since their spontaneous curvatures are typically not the same, this compositional asymmetry generally entails bending torques, which can be counteracted by differential stress—the difference between the two leaflet tensions. This stress, in turn, can affect elastic parameters or phase behavior of the membrane or each individual leaflet, or push easily flippable species, especially cholesterol, from the compressed leaflet into the tense leaflet. In short, breaking the symmetry of a single observable (to wit: composition), essentially breaks all other symmetries as well, with many potentially interesting consequences. This brief report examines the elastic aspects of this interplay, focusing on some elementary conditions of mechanical and thermodynamic equilibrium, but also shows how this poses novel questions that we are only beginning to appreciate.