Torsional energy can be taken up by alternative DNA conformations

The energy introduced into DNA by twisting has great potential as a regulatory mechanism, since the free energy can be stored in a variety of different high-energy conformations along the chain.

SAQ 14

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3.1 The helical structure of DNA

Having outlined the general principles of nucleic acid structures, we will now focus on how these principles influence the formation of specific structures found in DNA.

The helical structure of DNA arises because of the specific interactions between bases and the non-specific hydrophobic effects described earlier. Its structure is also determined through its active synthesis; that is, duplex DNA is synthesised by specialist polymerases upon a template strand. Within the helix, the two
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Summary of Section 2

  1. Nucleic acids are intrinsically highly flexible molecules.

  2. The chemical properties of nucleic acid components are primary determinants in structure formation.

  3. The formation of nucleic acid structures is driven by base pairing and stacking interactions between the hydrophobic bases. In DNA, these interactions drive the formation of the double helix, whose structure is maintained under torsional stress by twisting. RNA second
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2.4 Analysis of nucleic acids by electrophoresis and hybridisation

Nucleic acids can be separated according to size by gel electrophoresis, most commonly performed using a horizontal gel (Figure 7a). This is in contrast to the vertical gel electrophoresis set-up, which is generally used for analysis of proteins.

The size of DNA molecules is usually expressed in terms of the number of
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2.3 Analysing nucleic acid structures

In studying nucleic acid structures, many different experimental approaches can be adopted. In many cases, nucleic acid structures are examined in vitro, under non-physiological conditions, such as after denaturation or chemical synthesis. Nucleic acids within a cell are formed under very specific conditions and the structures that they adopt are influenced not only by the nature of their synthesis (by DNA or RNA polymerases), but by ancillary proteins that influence their folding. Nev
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Base pairing

Nucleic acid folding patterns are dominated by base pairing, which results from the formation of hydrogen bonds between pairs of nucleotides. In nucleic acids, as in proteins, the highly directional nature of this hydrogen bonding is the key to secondary structure.

SAQ 5


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2.2 General features of higher-order nucleic acid structure

Polynucleotide chains are intrinsically flexible molecules and have the potential to form many different higher-order structures. Their flexibility derives from rotation around bonds in the sugar-phosphate backbone (Figure 3b). In vivo, the structures that form are obviously determined by both the proteins that synthesise the nucleic acid chains (polymerases) and the ancillary proteins that bind to and modify them. We will discuss these aspects of structure later in this unit. What dri
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2.1 The primary structure of nucleic acids

We now know the detail of the order of individual bases, i.e. the genome sequence, of many of the organisms listed in Table 1. In Section 2 we will focus on the structures of nucleic acids within the cell, and we will start this discussion by outlining some of the general principles that apply to all nucleic acid structures.
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1.3 Nucleic acids and the flow of genetic information

The ‘flow’ of information from an organism's genome to the synthesis of its encoded proteins is referred to as the central dogma and emphasises the crucial roles that nucleic acids play within the cell (Figure 2). The synthesis of proteins (translation) is directed by the base order in mRNA, copied directly from that in the DNA of the genes by transcription. Translation involves RNAs in the form of the ribosome and tRNAs. In this unit we will be focusing on the relationship between
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1.2 Nucleic acids: genetic, functional and structural roles in the cell

The first role that one immediately thinks about for nucleic acids is that of an inherited genetic material, principally in the form of DNA. In some cases, the inherited genetic material is RNA instead of DNA. For example, almost 60% of all characterised viruses have RNA genomes and these are more common in plant viruses than in animal viruses. There is considerable variation in the amount of genetic material present within organisms (Author(s): The Open University

1.1 Early observations

Some of the earliest observations of macromolecules within living cells were of nucleic acids in the form of chromosomes. These long dark-staining objects, which became visible in the nucleus of cells at specific stages of cell division, were large enough to be detected using primitive light microscopes. Giant polytene chromosomes, found in certain cells such as the salivary gland cells of Drosophila (see Figure 1a), contain many thousands of copies of each chromosomal DNA align
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3.4 Second messengers

In the previous section, we have discussed the principles of second messengers (Section 1.5) and, in particular, those produced by PLC (IP3 and DAG) and PI3 kinase (PI(3,4)P2 and PI(3,4,5)P3). We shall now consider the roles and mechanisms of action of the other chief mediators, which are Ca2+ ions, cAMP and cGMP
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3.3 Lipid-modifying enzymes

The internal surface of the plasma membrane provides a useful environment for spreading signals received by surface receptors around the cell. Several specialist enzymes are activated by membrane-bound receptors, creating large numbers of small lipid-soluble second messenger molecules, which can diffuse easily through the membrane. These enzymes all use phosphatidylinositol (PI) and its derivatives as their substrates. PI itself is a derivative of glycerol: the OH group on carbon atom
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3.1 Introduction

We are now ready to describe in detail the major intracellular signalling pathways responsible for relaying the signal from the surface receptor to evoke a cellular response. This section will deal with signalling molecules that operate at the cytosolic leaflet of the plasma membrane (trimeric G proteins, monomeric G proteins and lipid-modifying enzymes), second messengers (such as Ca2+, cAMP, cGMP), protein kinases and phosphatases, and finally transcription factors.


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2.4 Receptor inactivation

As with all signalling components, receptors need to be switched off as well as on. Receptor inactivation can operate in several ways including removal of the ligand by degradation or sequestration, and desensitization of the target cell.

Binding of a ligand to its receptor is a reversible process, as the ligand will ultimately dissociate from the receptor and may be degraded. Acetylcholine is a good example of a signal regulated in this way; it is degraded by the enzyme cholinesterase
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2.3.4 Recruiter receptors

Enzyme-associated or recruiter receptors also form dimers (or oligomers) on activation by their ligand, in a similar way to receptors with intrinsic enzymatic activity. Dimerization facilitates an interaction between the cell surface receptor (which lacks a catalytic domain) and cytosolic proteins with enzymatic activity. In the case of receptors that associate with tyrosine kinases (called ‘tyrosine kinaseassociated receptors’, the most common in this group), it is the non-covalently lin
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2.3.3 Receptors with intrinsic enzymatic activity

Receptors with intrinsic enzymatic activity are the second biggest group of receptors after the GPCRs. They include four types according to the form of enzymatic activity of the intracellular domain (Figure 23a).

  • Receptor tyrosine kinases (RTKs) On activation, the kinase domain phosphorylates tyrosine amino
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2.3.2 Seven-helix transmembrane (7TM) receptors

Although in unicellular organisms such as the yeast S. cerevisiae there are only two classes of 7TM receptors, the pheromone and glucose receptors, multicellular organisms have many more, accounting for up to 5% of all genes in C. elegans and 2% of genes in the human and Drosophila genomes. 7TM proteins have been classified into four classes, A, B, C (Table 1). Between them, they can bind a huge range of ligands including simple ions, nucleotides, lipids, steroids, modifi
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2.3 Receptor activation

Receptors may be activated by conformational change (for example, ion-channel receptors such as nicotinic receptors, and 7TM receptors such as muscarinic receptors and adrenergic receptors), by formation of dimers (such as receptors with intrinsic enzymatic activity and recruiter receptors) or by proteolysis. We shall now consider how each cell surface receptor class described in Author(s): The Open University

2.1 Introduction

Every receptor has to be able to recognize its particular ligand in a specific manner, and become activated by it in such a way that it transmits the signal to the cell. We shall deal with receptor specificity and activation mechanisms. Then we shall see how the same principles of specificity and activation also apply to intracellular receptors.


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