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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1.6 Signalling proteins can act as molecular switches

How does a signalling molecule actually convey a signal? With second messengers, it is easy to understand: they are produced or released in large quantities, diffuse to their target, to which they usually bind, bringing about a functional change, after which they are degraded or stored within a subcellular compartment (such as endoplasmic reticulum). With signalling proteins it is less obvious. Protein concentrations cannot fluctuate rapidly, and protein molecules cannot easily move within th
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1.3 Most receptors are on the cell surface

Water-soluble signalling molecules cannot cross the membrane lipid bilayer, but bind to specific receptors embedded in the plasma membrane. The receptors have an extracellular domain that binds the signalling molecule, a hydrophobic transmembrane domain and an intracellular domain.

Binding of a ligand induces a conformational change in the receptor, in particular that of its intracellular region. It is this conformational change that activates a relay of intracellular signalling molecul
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1.2.2 Cell–cell signalling via secreted molecules

Extracellular signalling molecules are all fairly small, and are easily conveyed to the site of action; they are structurally very diverse. The classification and individual names of these mainly water-soluble mediators often reflect their first discovered action rather than their structure. So, for example, growth factors direct cell survival, growth and proliferation, and interleukins stimulate immune cells (leukocytes). However, to complicate matters further, they often have different effe
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1.2.1 Cell–cell contact-dependent signalling

In some instances, cells may communicate directly with their immediate neighbour through gap junctions (Figure 3a). Communication via gap junctions partially bypasses the signalling model we have outlined above in Figure 2. Gap junctions connect the cytoplasm of neighbouring cells via protein channels, which allow the passage of ions and small molecules (s
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1.1 Introduction

The fundamental principles of signalling can be illustrated by a simple example in the yeast S. cerevisiae (Figure 1). In order to sexually reproduce, a yeast cell needs to be able to make physical contact with another yeast cell. First, it has to ‘call’ to yeast cells of the opposite mating type. It does this by secreting a ‘mating factor’
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Introduction

Even the simplest organisms can detect and respond to events in their ever-changing environment. Similarly, within a multicellular organism, cells are surrounded by an extracellular environment from which signals are received and responded to. Extracellular events are decoded and transmitted to relevant parts of individual cells by way of a series of activation/deactivation steps involving many intracellular molecules. This relay of information along molecular pathways is called signal tra
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4.1 The Milky Way

Figure 1 showed two spiral galaxies: NGC 5548, which has an active nucleus, and NGC 3277 which does not. If we accept that AGN are the result of accretion on to supermassive black holes at the centres of the galaxies which harbour them, it is natural to ask the question whether galaxies like NGC 3277, which do not
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3.5 Example 1

(a) A gravitationally bound uniform density sphere, of radius r, is composed of a large number of subelements, with total mass M. Use the virial theorem,

The gravitational energy is given byAuthor(s): The Open University

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