The seat of a eukaryotic cell is the nucleus and most of the cellular information and instructions are stored there in the form of DNA (deoxyribonucleic acid). DNA, which is twisted, rolled, and linked into a two-meter-long chain, along with protein molecules, makes up a chromatin fiber that lies inside the nucleus. For years, scientists have been interested in how these components are organized. How is it possible for the proteins necessary in biochemical reactions to move efficiently inside a nucleus full of DNA? Recent research has finally solved the mystery. Findings describing them in detail are published in Journal of Physical Chemistry Letters December 21, 2020
Molecules in a crowded nucleus
The nucleus of each cell hides a chain two meters long of the most amazing and unique molecule: DNA. Together with histones and various related proteins, DNA builds a chromatin framework filled with a viscous fluid that shows excellent diversity of molecular composition. For decades, the mobility of molecules in the nucleus has not been sufficiently explored, but recent events have changed this status quo. Thanks to in-depth research by a group of researchers from the Institute of Physical Chemistry of the Polish Academy of Sciences (IPC PAS), led by Professor Robert Hołyst, the mobility of molecules at a length of one to ten nanometers in the nucleus is presented in detail.
Due to its small size, it could be assumed that the nucleus has a simple structure and a random distribution of molecules. That is by no means the case. The core has an incredibly complex and finely tuned layout. The DNA is not reminiscent of a messy web of spaghetti; it is efficiently packaged in compact structures. Even the viscosity of the core at the nanoscale level determines the mobility of individual objects from the inside. To better visualize how well all this is organized, the core can be described as a super store. Chromatin fibers act like shelves and contain a range of necessary genetic information (i.e. DNA) just like store shelves are filled with products. These shelves do not take up the entire space, but are separated inside the passage that serves as a channel. People who cross pass in certain patterns while shopping could be compared to protein molecules that move somewhat randomly within the nucleus channel according to the rules of Brownian motion. No matter how crowded the passage is, people always find a way to pass each other, keeping some distance as they walk. Molecules that cross molecular channels do the same without any traffic problems along the way. This allows each molecule to travel efficiently, while maintaining the tidiness of the supermarket.
Influence of viscosity
The molecules present in eukaryotic cells have different sizes. For example, ions are the size of a subnanometer, and protein radii are usually a few nanometers; the radius of the nucleosome is about 5.5 nm, while the folded chromatin fibers have a radius of about 15 nm. Furthermore, the compact chromatin loops form compact higher-level structures, which boast a radius of about 150 nm. To understand their mobility within the nucleus, Professor Hołyst’s team suggested that nanometer-sized objects be placed that cover the entire spectrum of scales of length of the natural components found in the nucleus. Polymers, proteins and nanoparticles with radii from 1.3 to 86 nm were considered.
To see this intriguing organization at the nanoscale level, the mobility of specific molecules was studied using noninvasive techniques such as fluorescence correlation spectroscopy (FCS) and raster image correction spectroscopy (RICS). Thanks to substances such as GFP (green fluorescent protein) or rhodamine-based nanoparticles in nanomolar concentration, it was possible to observe the mobility of individual molecules and determine the viscosity of the nucleoplasm without causing disturbances in cellular activity. These techniques allow scientists to investigate even the smallest changes at the molecular level. The mobility of large nanoparticles is reduced by as much as 6 times compared to diffusion in an aqueous medium.
However, the typical diffusion of protein-sized molecules is reduced only 2-3 times. Mobility decreases drastically when the radius of the injected objects is greater than 20, which is more important in diffusion coefficient estimates, it is possible to look more closely at the movement and interaction of molecules occurring between individual objects in nucleus channels and within packaged structures within the nucleus. These measurements expand our current understanding of core structure. A good understanding of the complexity of the channels within the nucleus is crucial because it directly contributes to our knowledge of how large biostructures, perhaps including medicine from the near future, are transmitted within the cell.
The first author, dr. Grzegorz Bubak notes: “Our experiments have revealed that the nucleus of eukaryotic cells is permeated through interchromosomal channels ~ 150 nm wide filled with an aqueous dilute solution of low viscosity protein.”
Studies that quantify congestion within cell nuclei reveal that most molecules can pass freely through this complex structure. Based on experiments supported by theoretical models, it was possible to estimate the channel width (~ 150 nm) between the chromatin structures. Nucleus channels can make up as much as 34% of the nucleus volume, which is about 240 fL. If they were narrower, the chromatin fibers would be scattered, which would prevent the efficient movement of molecules inside. It is fascinating that the nucleus can contain such large amounts of DNA and other chemical elements without interfering with the migration of molecules. This is all thanks to the well-arranged chromatin fibers that DNA creates with the structural proteins that give the double helix its shape. The mobility of certain chemical elements through biological fluid in molecular channels is essential in many processes, such as the formation of specific molecules and the formation of new protein complex structures.
“These results can be of great importance in the design of biological drugs such as therapeutic proteins, enzymes and monoclonal antibodies, which can have a hydrodynamic radius larger than conventional chemical drugs based on synthetic compounds,” concludes Dr. Bubak
As a result of these studies, the mobility of molecules in nuclear channels is now described in detail and well understood for the first time. Thanks to the research presented in this paper, we now know how chromatin fibers control the organization of molecules, revealing an intriguing molecular machinery hidden deep in the nucleus. We are now one step closer to developing therapeutic agents that can be efficiently transported to the nucleus.
Cells: Divide and enlarge
Grzegorz Bubak et al., Quantification of nanoscale viscosity and nucleus structure of living cells from mobility measurements, Journal of Physical Chemistry Letters (2020). DOI: 10.1021 / acs.jpclett.0c03052
Provided by the Polish Academy of Sciences
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