Molecular Biology

The development of new research methods significantly changed our views on the role that the 3D organization of the genome plays in its functional activity. It was found that the genome is subdivided into structural-functional units that restrict the area of enhancer action at the level of spatial organization. Spatial reconfiguration of an extended genomic fragment was identified as a potential mechanism that activates or represses various genes. Accordingly, a distorted spatial organization of the genome often causes various diseases, including cancer. All these observations contributed to the emergence of 3D genomics as a new avenue of research. The review summarizes the most important discoveries in the field of 3D genomics and discusses the directions of its further development.

Chromatin packing in eukaryotic chromosomes has been traditionally viewed as a hierarchical process, in which nucleosome chains fold into helical chromatin fibers. These fibers would then fold into more complex regular structures. However, recent chromatin imaging studies and analyses of chromosomal DNA contacts within the 3D space of the cell nucleus have necessitated a radical revision of the hierarchical chromatin packing model. According to the new studies, the nucleosome chain has a free spatial configuration without regular helical fibers in most cell types. The overall 3D organization of DNA in the cell nucleus includes chromatin loops and contact domains of up to several million base pairs in size. During cell differentiation, individual structure-functional chromatin domains marked by similar types of histone modifications and functional states can merge together and form chromosomal subcompartments suited for local gene activation or repression. This “attraction of likenesses” may be mediated by direct self-association of nucleosome chains as well as by architectural chromatin proteins making oligomeric protein “bridges” between nucleosomes as well as larger dynamic condensates leading to liquid–liquid phase separation inside the cell nucleus. Future studies of mechanisms of chromatin self-association and compartmentalization will require a combination of molecular, imaging, and computational approaches capable of revealing the 3D organization of the eukaryotic genome with nucleosomal resolution.

This review summarizes the main achievements of recent years in molecular organization research of yeast cell surface, i.e., the compartment that consists of the coordinately functioning plasma membrane, periplasmic space, and cell wall. There are data on vesicular transport to the external environment through the cell wall and the formation of channels in the wall, which indicate the possibility of dynamic rearrangements of the molecular structure of the yeast cell wall. There is an idea about the mosaic arrangement of the compartments of the plasma membrane. The hypothesis has been suggested on the heterogeneity of the molecular structure of the cell wall, which is usually considered as uniform except for the budding zones. The groups of proteins that form the molecular assembly of the yeast cell surface have been described. Special attention has been paid for proteins with amyloid properties, including Bgl2p glucanosyltransglycosylase, which is important for virulence in pathogenic yeast, and Gas1p, the first of the studied proteins of the cell surface, which is involved in the regulation of ribosomal DNA transcriptional silencing. The data on the structure of receptors localized on the cell surface and the “moonlight” proteins, involved in the cell stress response of yeasts, have been given.

Water soluble chlorophyll-binding proteins (WSCPs) of higher plants differ from most proteins containing chlorophyll or bacteriochlorophyll in that they are soluble in watr and are neither embedded in the lipid membrane nor directly involved in the process of photosynthesis. Chlorophyll molecules in WSCPs ensembles are packed in dimers within the hydrophobic zone of the protein matrix, similar to the structure of a chlorophyll “special pair” in the reaction centers of phototrophs. This fact together with the detected photosensitizing activity of WSCPs makes it possible to consider these proteins as a promising object for modelling the evolutionary prototypes of the photosynthetic apparatus, as well as for developing the artificial solar energy converters. There are two classes of proteins in the WSCP family, class I and class II the representatives of these classes have a weak degree of homology in the primary structure, but a high degree of similarity in the tertiary and quaternary structure. One of the features of class I WSCPs is photoconversion, that is, to change the structure and spectral properties of the chromophore under the action of light. The functions of WSCPs in the plant are thought to be associated with stress protection.

Advances in the research of molecular factors involved in the onset and progression of Alzheimer’s disease, have led to the creation of several pathogenesis concepts of the most common neurodegenerative disease in the world, and amyloid, cholinergic, and neuroinflammatory hypotheses became leading. Over past twenty years, based on these hypotheses, hundreds of drug prototypes were developed, but none of them were able to stop the development of Alzheimer’s disease. In this review, based on the latest experimental data on structure-function properties of chemically modified amyloid-beta isoforms, the concept of the origin and the mechanism of action of amyloid-beta with isomerized Asp7 residue, as a molecular agent of Alzheimer’s disease pathogenesis, is presented. This concept makes it possible not only to combine the most important aspects of existing hypotheses but also indicates ways of creating agents for fighting Alzheimer’s disease with a principally new mechanism of action, “disease-modifying drugs.”

The 26S proteasome is a multisubunit ATP-dependent protease complex and is necessary for the normal function of the eukaryotic cell and its survival in stress. Twenty years ago, we, in collaboration with German researchers, were the first to experimentally describe a system for coordinated regulation of proteasomal gene expression in the yeast Saccharomyces cerevisiae. This system consists of the ScRpn4 transcription factor and its binding site, called PACE. Based on the results of a bioinformatics search in the first sequenced yeast genomes, Rpn4-like proteins and PACE-like elements were postulated for other species of the class Saccharomycetes. We experimentally characterized Rpn4-like proteins in the biotechnologically significant yeast species Komagataella pfaffii (Pichia pastoris), Yarrowia lipolytica, and Debaryomyces hansenii and the opportunistic yeast Candida glabrata. As ample information accumulates for the genome sequences of new yeast species and strains, the question arises as to how diverse the regulatory system of proteasomal genes is in terms of structure and likely mechanisms of function. In this work, a bioinformatics search for Rpn4-like proteins and PACE-like elements was conducted in 3111 strains belonging to 427 yeast species of the class Saccharomycetes. It was shown that only the DNA-binding domain is conserved among Rpn4-like proteins, in accordance with conservation of PACE elements. Certain systems were found to contain more than one Rpn4-like protein with structural differences in the DNA-binding domain or to include an autoregulation of the genes for Rpn4-like proteins. Given that Rpn4-like proteins and proteasomes play a role in the cell response to stress, the diversity of systems for the regulation of proteasomal genes was assumed to corresponds to adaptation of organisms to their living environments.

Zinc ions and glycosaminoglycans (GAGs) are found in amyloid deposits and are known to modulate the β-amyloid peptide (Аβ) aggregation, which is thought to be a key event in the pathogenesis of Alzheimer’s disease (AD). Correlation spectroscopy was used to study how the H6R and D7H mutations of the metal-binding domain (MBD) of Аβ42 affect the modulation of its zinc-induced aggregation by the model GAG heparin. The H6R mutation was shown to decrease and the D7H mutation to increase the Аβ42 propensity to aggregate in the presence of zinc ions. In addition, H6R diminished and D7H enhanced the modulating effect of heparin. The difference in the heparin-dependent modulation was associated with coordination of zinc ions within the MBDs of the mutant peptides. The findings indicate that anion-binding sites formed by complexes of zinc ions with the Аβ MBD play an essential role in the interaction of zinc-induced Аβ aggregates with heparin.