3 DNA: Spot the difference Here we look at DNA, the molecule which contains the instructions for making each living creature. It is contained within the genes of every individual living thing on Earth. Closely related creatures have DNA that is very similar, and distantly related creatures have DNA that is very different. By looking at how similar or different their DNA molecules are, we can see how closely related two species are. 2 Odd one out The image below shows models of four mammals: Rhinoceros Whale Elephant Hippopotamus 4.2 Peptide signal sequences The distinct chemistry of proteins at the N- and C-termini provides protein molecules with two positionally and chemically unique sites for post-translational modifications and with the means to control their spatial and temporal interactions and position. This feature of proteins is crucial for a variety of biological processes from protein degradation to protein sorting for specific cellular compartments. The N- and C-termini of proteins have distinct roles, and we have already emphasised t 4.2 Summary Glycogen metabolism is controlled by two enzymes, glycogen synthase (mediating glycogen synthesis) and phosphorylase (mediating glycogen breakdown). Three pathways converge in the regulation of glycogen synthase: cAMP/PKA and GSK-3β are negative regulators, whereas ISPK/PP1G positively regulate the activity of glycogen synthase. Insulin and adrenalin have opposite effects on glycogen synthesis: insulin promotes glycogen synthes 3.9 Summary Heterotrimeric G proteins are tethered to the internal surface of the plasma membrane, and are activated by conformational change within 7TM receptors. There are many different α subunits (and a few βγ subunits), which interact with different receptors and different effectors. The major targets of G proteins include ion channels, adenylyl cyclase (activated by Gαs and inhibited by Gαi) and PLC-β (activated by Gαq). 3.6.2 The JAK–STAT pathway Another important protein kinase pathway is the JAK–STAT pathway. Cytokines (Section 2.2), are frequently used for signalling between cells of the immune system. Cytokine-induced signal transduction cascades are often direct pathways to the nucleus for switching on sets of genes. Janus kinases (JAKs, named after the two-faced Roman god) are a particular 3.4.2 Cyclic AMP The concentration of cyclic AMP (cAMP) in the cytosol increases 20-fold within seconds of an appropriate stimulus. This is achieved by the action of the plasma membrane-embedded protein adenylyl cyclase, which synthesizes cAMP from ATP (Figure 34). cAMP is short-lived, as with all second messengers, because it is continuously degraded by 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. 1.8 Protein–protein interactions in signal transduction Many signalling proteins have both a catalytic domain and sometimes several binding domains.Some only have binding domains, enabling their proteins to act as adaptor, scaffold or anchoring proteins to bring other proteins together. Because of this multiplicity of binding domains, signalling proteins can potentially combine to form complexes with many other proteins; these complexes may be either transient (e.g. in response to stimulation by a growth factor), or stable (to target a protein to 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 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 References 6.6 Summary of Section 6 The majority of proteins of known function are enzymes. Enzymes are biological catalysts, increasing the rates of reactions. Enzymes are not permanently altered by catalysis of a reaction. The transition state is an unstable intermediate enzyme–substrate complex in which the enzyme and the substrate are in highly strained conformations. There are a number of different catalytic mechanisms employed by enzymes including general 5.5 Summary of Section 5 Proteins are dynamic molecular machines. All proteins bind to other molecules, whether ions, small molecules or macromolecules, and these interactions are critical to the protein's function. The activity of proteins is regulated by changes in conformation. In allosterically regulated proteins, binding of one ligand affects the conformation of a remote part of the protein, thereby regulating interaction with a second ligand. Cooperative binding 5.3.2 Cooperative binding A feature of some proteins comprising more than one subunit is that binding of a ligand to its binding site on one subunit, can increase the affinity of a neighbouring subunit for the same ligand, and hence enhance binding. The ligand-binding event on the first subunit is communicated, via conformational change, to the neighbouring subunit. This type of allosteric regulation is called cooperative binding. Haemoglobin, as we have already discussed, is a tetramer consisting of two 5.2 All proteins bind other molecules All proteins bind to other molecules (generically termed ligands). Ligands that can bind to proteins include: ions, e.g. Ca2+; small molecules, e.g. H2O, O2 and CO2, glucose, ATP, GTP, NAD; macromolecules, i.e. proteins, lipids, polysaccharides, nucleic acids. These interactions are specific and key to the protein's function and, of course, are critically d 5.1 Introduction In some ways, proteins can be thought of as molecular machines, that through evolution have become highly specialised and efficient. Despite the somewhat static representations of proteins that you have met so far, proteins are in fact dynamic molecules. Not only are there internal movements, with conformational changes that are integral to protein function and regulation of function, but proteins, by virtue of their specific interactions with other cellular components, are essential to all t 3.4 The functional domains of Src To illustrate some of the principles of multidomain protein function, we will use as an example, the Src protein, a very well-characterised tyrosine kinase. As described earlier, Src contains four domains: two kinase domains, which together comprise the catalytic component of this protein, and two distinct binding/regulatory domains. The binding domains are of the SH2 and SH3 types. The identification of domains in other proteins, homologous to those in Src, led to the ‘Src ho 1.6 Fibrous proteins Most of the proteins described so far have been globular proteins. There are, however, some distinctive features that characterise fibrous proteins and we present here a general overview of these. Elongated fibrous proteins frequently play a structural role in the cell. They do not readily crystallise but tend to aggregate along their long axis to form fibres. X-ray diffraction studies of these fibres, in contrast to analysis of protein crystals, provides only very limited information on the 1.4.4 Covalent cross-linkages stabilise protein structure Proteins that are secreted by the cell, or are attached to the extracellular surface of the plasma membrane, can be subject to more extreme conditions than those experienced by intracellular proteins. Often, covalent cross-linkages stabilise these proteins by connecting specific amino acids within a polypeptide or between polypeptide chains in multisubunit proteins (see below). Typically such a linkage will be a covalent sulfur–sulfur bond which forms between the –SH groups of two cystein
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Author(s):
Author(s):
Huse, M. and Kuriyan, J. (2002) The conformational plasticity of protein kinases, Cell, 109, pp. 275–282.
Lipscomb, W. N., Reeke, G. N. Jr, Hartsuck, J. A., Quiocho, F. A. and Bethge, P. H. (1970) The structure of carboxypeptidase A. 8. Atomic interpretation at 0.2 nm resolution, a new study of the complex of glycyl-L-tyrosine with CPA, and mechanistic deductio
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