Nucleic acid quaternary structure

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The image above contains clickable links Interactive image of nucleic acid structure (primary, secondary, tertiary, and quaternary) using DNA helices and examples from the VS ribozyme and telomerase and nucleosome. (PDB: ADNA, 1BNA, 4OCB, 4R4V, 1YMO, 1EQZ ) DNA RNA structure (4).png
The image above contains clickable links Interactive icon.svg
The image above contains clickable links
Interactive image of nucleic acid structure (primary, secondary, tertiary, and quaternary) using DNA helices and examples from the VS ribozyme and telomerase and nucleosome. ( PDB: ADNA, 1BNA, 4OCB, 4R4V, 1YMO, 1EQZ ​)
DNA coils and winds around histone proteins to condense into chromatin.

Nucleic acidquaternary structure refers to the interactions between separate nucleic acid molecules, or between nucleic acid molecules and proteins. The concept is analogous to protein quaternary structure, but as the analogy is not perfect, the term is used to refer to a number of different concepts in nucleic acids and is less commonly encountered. [1] Similarly other biomolecules such as proteins, nucleic acids have four levels of structural arrangement: primary, secondary, tertiary, and quaternary structure. Primary structure is the linear sequence of nucleotides, secondary structure involves small local folding motifs, and tertiary structure is the 3D folded shape of nucleic acid molecule. In general, quaternary structure refers to 3D interactions between multiple subunits. In the case of nucleic acids, quaternary structure refers to interactions between multiple nucleic acid molecules or between nucleic acids and proteins. Nucleic acid quaternary structure is important for understanding DNA, RNA, and gene expression because quaternary structure can impact function. For example, when DNA is packed into heterochromatin, therefore exhibiting a type of quaternary structure, gene transcription will be inhibited.

Contents

DNA

DNA quaternary structure is used to refer to the binding of DNA to histones to form nucleosomes, and then their organisation into higher-order chromatin fibres. [2] The quaternary structure of DNA strongly affects how accessible the DNA sequence is to the transcription machinery for expression of genes. DNA quaternary structure varies over time, as regions of DNA are condensed or exposed for transcription. The term has also been used to describe the hierarchical assembly of artificial nucleic acid building blocks used in DNA nanotechnology. [3]

The quaternary structure of DNA refers to the formation of chromatin. Because the human genome is so large, DNA must be condensed into chromatin, which consists of repeating units known as nucleosomes. Nucleosomes contain DNA and proteins called histones. The nucleosome core usually contains around 146 DNA base pairs wrapped around a histone octamer. [4]  The histone octamer is made of eight total histone proteins, two of each of the following proteins: H2A, H2B, H3, and H4. [5]  Histones are primarily responsible for shaping the nucleosomes, therefore drastically contributing to chromatin structure. [4]  Histone proteins are positively-charged and therefore can interact with the negatively-charged phosphate backbone of DNA. [5]  One portion of core histone proteins, known as histone tail domains, are extremely important for keeping the nucleosome tightly wrapped and giving the nucleosome secondary and tertiary structure. This is because the histone tail domains are involved in interactions between nucleosomes. The linker histone, or H1 protein, is also involved maintaining nucleosome structure. The H1 protein has the special role of ensuring that DNA stays tightly wound. [4]

Modifications to histone proteins and their DNA are classified as quaternary structure. Condensed chromatin, heterochromatin, prevents transcription of genes. In other words, transcription factors cannot access wound DNA- [6]  This is in contrast to euchromatin, which is decondensed, and therefore, readily accessible to the transcriptional machinery. DNA methylation to nucleotides influences chromatin quaternary structure. Highly methylated DNA nucleotides are more likely found within heterochromatin whereas unmethylated DNA nucleotides are common in euchromatin. Furthermore, post-translational modifications can be made to the core histone tail domains, which lead to changes in DNA quaternary structure and therefore gene expression. Enzymes, known as epigenetic writers and epigenetic erasers, catalyze either the addition or removal of several modifications to the histone tail domains. For instance, an enzyme writer can methylate Lysine-9 of the H3 core protein, which is found in the H3 histone tail domain. This can lead to gene repression as the chromatin gets remodeled and resembles heterochromatin. However, dozens of modifications can be made to histone tail domains. Therefore, it is the sum of all those modifications that determine whether chromatin will resemble heterochromatin or euchromatin. [7]

The three-dimensional folding motif known as the kissing loop. In this diagram, two kissing loop models are overlaid to show structural similarities. The white backbone and pink bases are from B. subtilis, and the gray backbone and blue bases are from V. vulnificus. Kissing Loop Motif Overlay.png
The three-dimensional folding motif known as the kissing loop. In this diagram, two kissing loop models are overlaid to show structural similarities. The white backbone and pink bases are from B. subtilis, and the gray backbone and blue bases are from V. vulnificus.
A Minor Motif interaction A-minor-motif type1.png
A Minor Motif interaction

RNA

RNA is subdivided into many categories, including messenger RNA (mRNA), ribosomal RNA (rRNA), transfer RNA (tRNA), long non-coding RNA (lncRNA), and several other small functional RNAs. Whereas many proteins have quaternary structure, the majority of RNA molecules have only primary through tertiary structure and function as individual molecules rather than as multi-subunit structures. [1] Some types of RNA show clear quaternary structure that is essential for function, whereas other types of RNA function as single molecules and do not associate with other molecules to form quaternary structures. Symmetrical complexes of RNA molecules are extremely uncommon compared to protein oligomers. [1] One example of an RNA homodimer is the VS ribozyme from Neurospora, with its two active sites consisting of nucleotides from both monomers. [9] The best known example of RNA forming quaternary structures with proteins is the ribosome, which consists of multiple rRNAs, supported by rProteins. [10] [11] Similar RNA-Protein complexes are also found in the spliceosome.

Riboswitches

Riboswitches are a type of mRNA structure that help regulate gene expression and often bind a diverse set of ligands. Riboswitches determine how gene expression responds to varying concentrations of small molecules in the cell [12] This motif has been observed in flavin mononucleotide (FMN), cyclic di-AMP (c-di-AMP), and glycine. Riboswitches are said to show pseudoquaternary structure. Several structurally similar regions of a single RNA molecule fold together symmetrically. Because this structure arises from a single molecule and not from multiple separate molecules, it cannot be referred to as true quaternary structure. [1] Depending on where a riboswitch binds and how it is arranged, it can suppress or allow a gene to be expressed [12] Symmetry is an important part of biomolecular three-dimensional configurations. Many proteins are symmetrical on the level of quaternary structure, but RNAs rarely have symmetrical quaternary structures. Even though tertiary structure is variant and essential for all types of RNAs, RNA oligimerization is relatively rare. [1]

rRNA

Ribosomes, the organelle for protein translation takes place, are made out of rRNA and proteins. Ribosomes may be the best and most abundant example of nucleic acid quaternary structure. The specifics of ribosome structure varies among different kingdoms and species, but all ribosomes are made of a large subunit and a small unit. Different classes of organisms have ribosomal subunits of different characteristic sizes. The three dimensional association of ribosomal subunits is essential for ribosomal function. The small subunit binds first to mRNA and then the large subunit is recruited. In order for a polypeptide to be formed, proper association of the mRNA and both of the ribosome subunits must occur. At left, the secondary structure of rRNA in the peptidyltransferase center of the ribosome in yeast. The peptidyltransferase center is where the formation of the peptide bond is catalyzed during translation. At right, the three-dimensional structure of the peptidyltransferase center. The helical rRNA is associated with globular ribosomal proteins. Incoming codons arrive at the A site and move to the P site, where peptide bond formation is catalyzed. One specific three dimensional structure that is commonly observed in rRNA is the A-minor motif. There are four types of A-minor motifs, all of which include many unpaired adenosines. These lone adenosines extend from outward and allow RNA molecules to bind other nucleic acids in the minor groove. [1]

tRNA

While consensus secondary and tertiary structures have been observed in tRNAs, there has not been evidence of tRNAs creating a quaternary structure thus far. [1] Of note, it has been observed through high resolution imaging that tRNA interacts with the quaternary structure of bacterial 70S ribosome and other proteins. [13] [12]

Other small RNAs

pRNA

Bacteriophage φ29 prohead RNA (pRNA) has the ability to form quaternary structure. [1] pRNA is able to form into a quaternary structure by oligimerizing to create the capsid that encloses the genomic DNA of bacteriophage. Several molecules of pRNA surround the genome, and through stacking interactions and base pairing the pRNAs enclose and the protect the DNA. [1] Crystallography studies show that pRNA forms tetrameric rings, although cryo-EM structures suggest pRNA may also form pentameric rings. [14]

Kissing loop Motif

In this model, based on Dengue Virus Methyltransferase, four monomers of methyltransferase surround two octamers of RNA. The nucleic acid associations demonstrate the kissing loop motif. The three-dimensional folding motif known as the kissing loop. In this diagram, two kissing loop models are overlaid to show structural similarities. The white backbone and pink bases are from B. subtilis, and the gray backbone and blue bases are from V. vulnificus.

The kissing loop motif has been observed in retroviruses and RNAs that are encoded by plasmids. [12] The determination of the number of kissing loops to form the capsid varies between 5 and 6. Five kissing loops have been shown to have a stronger stability due to the particular symmetry that the 5 kissing loop structure provides.

Small nuclear RNA

Small nuclear RNA (snRNA) combines with proteins to form the spliceosome in the nucleus. The spliceosome is responsible for sensing and cutting introns out of pre-mRNA, which is one of the first steps of mRNA processing. The spliceosome is a large macromolecular complex. Quaternary structure allows snRNA to detect mRNA sequences that need to be excised. [15]

Related Research Articles

Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in reinforcing the DNA during cell division, preventing DNA damage, and regulating gene expression and DNA replication. During mitosis and meiosis, chromatin facilitates proper segregation of the chromosomes in anaphase; the characteristic shapes of chromosomes visible during this stage are the result of DNA being coiled into highly condensed chromatin.

<span class="mw-page-title-main">Nucleosome</span> Basic structural unit of DNA packaging in eukaryotes

A nucleosome is the basic structural unit of DNA packaging in eukaryotes. The structure of a nucleosome consists of a segment of DNA wound around eight histone proteins and resembles thread wrapped around a spool. The nucleosome is the fundamental subunit of chromatin. Each nucleosome is composed of a little less than two turns of DNA wrapped around a set of eight proteins called histones, which are known as a histone octamer. Each histone octamer is composed of two copies each of the histone proteins H2A, H2B, H3, and H4.

<span class="mw-page-title-main">Protein biosynthesis</span> Assembly of proteins inside biological cells

Protein biosynthesis is a core biological process, occurring inside cells, balancing the loss of cellular proteins through the production of new proteins. Proteins perform a number of critical functions as enzymes, structural proteins or hormones. Protein synthesis is a very similar process for both prokaryotes and eukaryotes but there are some distinct differences.

<span class="mw-page-title-main">RNA</span> Family of large biological molecules

Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself or by forming a template for the production of proteins. RNA and deoxyribonucleic acid (DNA) are nucleic acids. The nucleic acids constitute one of the four major macromolecules essential for all known forms of life. RNA is assembled as a chain of nucleotides. Cellular organisms use messenger RNA (mRNA) to convey genetic information that directs synthesis of specific proteins. Many viruses encode their genetic information using an RNA genome.

<span class="mw-page-title-main">Euchromatin</span> Lightly packed form of chromatin that is enriched in genes

Euchromatin is a lightly packed form of chromatin that is enriched in genes, and is often under active transcription. Euchromatin stands in contrast to heterochromatin, which is tightly packed and less accessible for transcription. 92% of the human genome is euchromatic.

A regulatory sequence is a segment of a nucleic acid molecule which is capable of increasing or decreasing the expression of specific genes within an organism. Regulation of gene expression is an essential feature of all living organisms and viruses.

The histone fold is a structural motif located near the C-terminus of histone proteins, characterized by three alpha helices separated by two loops. This motif facilitates the formation of heterodimers, which subsequently assemble into a histone octamer, playing a crucial role in the packaging of DNA into nucleosomes within chromatin. This fold is an ancient and highly conserved structural motif, essential for DNA compaction and regulation across a wide range of species.

<span class="mw-page-title-main">DNA-binding protein</span> Proteins that bind with DNA, such as transcription factors, polymerases, nucleases and histones

DNA-binding proteins are proteins that have DNA-binding domains and thus have a specific or general affinity for single- or double-stranded DNA. Sequence-specific DNA-binding proteins generally interact with the major groove of B-DNA, because it exposes more functional groups that identify a base pair.

<span class="mw-page-title-main">Ribosomal RNA</span> RNA component of the ribosome, essential for protein synthesis in all living organisms

Ribosomal ribonucleic acid (rRNA) is a type of non-coding RNA which is the primary component of ribosomes, essential to all cells. rRNA is a ribozyme which carries out protein synthesis in ribosomes. Ribosomal RNA is transcribed from ribosomal DNA (rDNA) and then bound to ribosomal proteins to form small and large ribosome subunits. rRNA is the physical and mechanical factor of the ribosome that forces transfer RNA (tRNA) and messenger RNA (mRNA) to process and translate the latter into proteins. Ribosomal RNA is the predominant form of RNA found in most cells; it makes up about 80% of cellular RNA despite never being translated into proteins itself. Ribosomes are composed of approximately 60% rRNA and 40% ribosomal proteins, though this ratio differs between prokaryotes and eukaryotes.

<span class="mw-page-title-main">Nucleoprotein</span> Type of protein

Nucleoproteins are proteins conjugated with nucleic acids. Typical nucleoproteins include ribosomes, nucleosomes and viral nucleocapsid proteins.

<span class="mw-page-title-main">Post-transcriptional modification</span> RNA processing within a biological cell

Transcriptional modification or co-transcriptional modification is a set of biological processes common to most eukaryotic cells by which an RNA primary transcript is chemically altered following transcription from a gene to produce a mature, functional RNA molecule that can then leave the nucleus and perform any of a variety of different functions in the cell. There are many types of post-transcriptional modifications achieved through a diverse class of molecular mechanisms.

<span class="mw-page-title-main">Histone H2A</span> One of the five main histone proteins

Histone H2A is one of the five main histone proteins involved in the structure of chromatin in eukaryotic cells.

<span class="mw-page-title-main">Biomolecular structure</span> 3D conformation of a biological sequence, like DNA, RNA, proteins

Biomolecular structure is the intricate folded, three-dimensional shape that is formed by a molecule of protein, DNA, or RNA, and that is important to its function. The structure of these molecules may be considered at any of several length scales ranging from the level of individual atoms to the relationships among entire protein subunits. This useful distinction among scales is often expressed as a decomposition of molecular structure into four levels: primary, secondary, tertiary, and quaternary. The scaffold for this multiscale organization of the molecule arises at the secondary level, where the fundamental structural elements are the molecule's various hydrogen bonds. This leads to several recognizable domains of protein structure and nucleic acid structure, including such secondary-structure features as alpha helixes and beta sheets for proteins, and hairpin loops, bulges, and internal loops for nucleic acids. The terms primary, secondary, tertiary, and quaternary structure were introduced by Kaj Ulrik Linderstrøm-Lang in his 1951 Lane Medical Lectures at Stanford University.

2-<i>O</i>-methylation

2'-O-methylation (2'-O-Me) is a common nucleotide epitranscriptomics modification of ribosomal RNA (rRNA). The rRNA is transcribed from DNA and then used to create proteins through translation. The resulting protein would normally be solely dependent on the gene it was translated from, but the methylation of the RNA would influence the outcome of the protein as well. This modification to the rRNA is done via ribonucleoprotein (snoRNP) where a methyl group is added to the 2' hydroxyl of the ribose moiety of any nucleotide (Nm) producing a methoxy group. The modification of one Nm creates more stabilization in the structure by 0.2kcal/mol which is more enthalpically favorable. 2'-O-methylated nucleotides are mostly found in post-translational ribosomal RNA and small nuclear RNA located in the ribosome and spliceosome. Currently, about 55 2'-O-methylations have been identified in yeast alone and 106 in humans and deposited in RNA Modification Base (RMBase) database.

<span class="mw-page-title-main">NoRC associated RNA</span> Non-coding RNA element

NoRC associated RNA is a non-coding RNA element which regulates ribosomal RNA transcription by interacting with TIP5, part of the NoRC chromatin remodeling complex.

<span class="mw-page-title-main">Nucleic acid tertiary structure</span> Three-dimensional shape of a nucleic acid polymer

Nucleic acid tertiary structure is the three-dimensional shape of a nucleic acid polymer. RNA and DNA molecules are capable of diverse functions ranging from molecular recognition to catalysis. Such functions require a precise three-dimensional structure. While such structures are diverse and seemingly complex, they are composed of recurring, easily recognizable tertiary structural motifs that serve as molecular building blocks. Some of the most common motifs for RNA and DNA tertiary structure are described below, but this information is based on a limited number of solved structures. Many more tertiary structural motifs will be revealed as new RNA and DNA molecules are structurally characterized.

<span class="mw-page-title-main">Nucleic acid structure</span> Biomolecular structure of nucleic acids such as DNA and RNA

Nucleic acid structure refers to the structure of nucleic acids such as DNA and RNA. Chemically speaking, DNA and RNA are very similar. Nucleic acid structure is often divided into four different levels: primary, secondary, tertiary, and quaternary.

Numerous key discoveries in biology have emerged from studies of RNA, including seminal work in the fields of biochemistry, genetics, microbiology, molecular biology, molecular evolution, and structural biology. As of 2010, 30 scientists have been awarded Nobel Prizes for experimental work that includes studies of RNA. Specific discoveries of high biological significance are discussed in this article.

H3Y41P is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the phosphorylation the 41st tyrosine residue of the histone H3 protein.

This glossary of cellular and molecular biology is a list of definitions of terms and concepts commonly used in the study of cell biology, molecular biology, and related disciplines, including molecular genetics, biochemistry, and microbiology. It is split across two articles:

References

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  2. ↑ Sipski ML, Wagner TE (March 1977). "Probing DNA quaternary ordering with circular dichroism spectroscopy: studies of equine sperm chromosomal fibers". Biopolymers. 16 (3): 573–82. doi:10.1002/bip.1977.360160308. PMID   843604. S2CID   35930758.
  3. ↑ Chworos A, Jaeger, Luc (2007). "Nucleic acid foldamers: design, engineering and selection of programmable biomaterials with recognition, catalytic and self-assembly properties". In Hecht S, Huc I (eds.). Foldamers: Structure, Properties, and Applications. Weinheim: Wiley-VCH-Verl. pp. 298–299. ISBN   978-3-527-31563-5.
  4. 1 2 3 Cutter AR, Hayes JJ (October 2015). "A brief review of nucleosome structure". FEBS Letters. 589 (20 Pt A): 2914–22. doi:10.1016/j.febslet.2015.05.016. PMC   4598263 . PMID   25980611.
  5. 1 2 Annunziato A (2008). "DNA Packaging: Nucleosomes and Chromatin". Nature Education. 1 (1): 26.
  6. ↑ Duggan NM, Tang ZI (2010). "The Formation of Heterochromatin and RNA interference". Nature Education. 3 (9): 5.
  7. ↑ Griffiths A (2015). Introduction to Genetic Analysis. W. H. Freeman and Company. ISBN   978-1464109485.
  8. ↑ Appasamy SD, Ramlan EI, Firdaus-Raih M (2013-09-05). "Comparative sequence and structure analysis reveals the conservation and diversity of nucleotide positions and their associated tertiary interactions in the riboswitches". PLOS ONE. 8 (9): e73984. Bibcode:2013PLoSO...873984A. doi: 10.1371/journal.pone.0073984 . PMC   3764141 . PMID   24040136.
  9. ↑ Suslov NB, DasGupta S, Huang H, Fuller JR, Lilley DM, Rice PA, Piccirilli JA (November 2015). "Crystal structure of the Varkud satellite ribozyme". Nature Chemical Biology. 11 (11): 840–6. doi:10.1038/nchembio.1929. PMC   4618023 . PMID   26414446.
  10. ↑ Noller HF (1984). "Structure of ribosomal RNA". Annual Review of Biochemistry. 53: 119–62. doi:10.1146/annurev.bi.53.070184.001003. PMID   6206780. S2CID   36722002.
  11. ↑ Nissen P, Ippolito JA, Ban N, Moore PB, Steitz TA (April 2001). "RNA tertiary interactions in the large ribosomal subunit: the A-minor motif". Proceedings of the National Academy of Sciences of the United States of America. 98 (9): 4899–903. Bibcode:2001PNAS...98.4899N. doi: 10.1073/pnas.081082398 . PMC   33135 . PMID   11296253.
  12. 1 2 3 4 Chen Y, Varani G (2010), "RNA Structure", eLS, American Cancer Society, doi:10.1002/9780470015902.a0001339.pub2, ISBN   9780470015902
  13. ↑ Koehler C, Round A, Simader H, Suck D, Svergun D (January 2013). "Quaternary structure of the yeast Arc1p-aminoacyl-tRNA synthetase complex in solution and its compaction upon binding of tRNAs". Nucleic Acids Research. 41 (1): 667–76. doi:10.1093/nar/gks1072. PMC   3592460 . PMID   23161686.
  14. ↑ Ding F, Lu C, Zhao W, Rajashankar KR, Anderson DL, Jardine PJ, et al. (May 2011). "Structure and assembly of the essential RNA ring component of a viral DNA packaging motor". Proceedings of the National Academy of Sciences of the United States of America. 108 (18): 7357–62. Bibcode:2011PNAS..108.7357D. doi: 10.1073/pnas.1016690108 . PMC   3088594 . PMID   21471452.
  15. ↑ Will CL, Lührmann R (July 2011). "Spliceosome structure and function". Cold Spring Harbor Perspectives in Biology. 3 (7): a003707. doi:10.1101/cshperspect.a003707. PMC   3119917 . PMID   21441581.
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