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Lecture 7

BCH2011: Textbook summary - Lecture 7

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Monash University

LECTURE 7 Quaternary Structures: Many proteins gave multiple polypeptide subunits (from two to hundreds). Many multisubunit proteins have regulatory roles; the binding of small molecules may affect the interaction between subunits, causing large changes in the protein’s activity in response to small changes in the concentration of substrate or regulatory molecules. A multisubunit protein is also referred to as a multimer. A multimer with just a few subunits is often called an oligomer. If a multimer has nonidentical subunits, the overall structure of the protein can be asymmetric and quite complicated. However, most multimers have identical subunits or repeating groups of nonidentical subunits usually in symmetric arrangements. The repeating structural unit in such a multimeric protein, whether a single subunit or a group of subunits, is called a protomer. Quaternary Structure of Haemoglobin: The first oligometric protein to have its 3D structure determined was haemoglobin, which contains four polypeptide chains and four heme prosthetic groups, in which the iron atoms are in the ferrous (Fe2+) state. The protein portion, the globin, consists of two alpha chains (141 residues each), and two beta chains (146 residues each). Note that these does not refer to the secondary structures. The subunits of haemoglobin are arranged in symmetric pairs, each pair having one alpha and one beta subunit. Haemoglobin can therefore be described either as a tetramer or as a dimer of alpha-beta protomers. Ligand: The functions of many proteins involve the reversible binding of other molecules. A molecule bound reversibly by a protein is called a ligand. A ligand may be any kind of molecule, including another protein. The transient nature of protein- ligand interactions is critical to life, allowing an organism to respond rapidly and reversibly to changing environmental and metabolic circumstances. A ligand binds at a site on the protein called the binding site, which is complementary to the ligand in size, shape, charge, and hydrophobic or hydrophilic character. Furthermore, the interaction is specific: the protein can discriminate among the thousands of different molecules in its environment and selectively bind only one or a few. A given protein may have separate binding sites for several different ligands. These specific molecular interactions are crucial in maintaining the high degree of order in a living system. Proteins are flexible. Changes in conformation may be subtle, reflecting molecular vibrations and small movements of amino acid residues throughout the protein. Changes in conformation may also be quite dramatic, with major segments of the protein structure moving as much as several nanometers. Specific conformational changes are frequently essential to a protein’s function. The binding of a protein and ligand is often coupled to a conformational change in the protein that makes the binding site more complementary to the ligand, permitting tighter binding. The structural adaptation that occurs between protein and ligand is called induced fit. In multisubunit protein, a conformational change in one subunit often affects the conformation of other subunits. Interactions between ligands and proteins may be regulated, usually through specific interactions with one or additional ligands. These other ligands may cause conformational changes in the protein that affect the binding of the first ligand. Enzymes represent a special case of protein function. Enzymes bind and chemically transform other molecules – they catalyse reactions. The molecules acted upon by enzymes are called reaction substrates rather than ligands, and the ligand-binding site is called the catalytic site or active site. Oxygen Can Bind to a Heme Prosthetic Group: Oxygen is poorly soluble in aqueous solutions and cannot be carried to tissues in sufficient quantity if it is simply dissolved in blood serum. Diffusion of oxygen through tissues is also ineffective over distances greater than a few millimeters. The evolution of larger, multicellular animals depended on the evolution of proteins that could transport and store oxygen. However, none of the amino acid side chains in proteins are suited for the reversible banding of oxygen molecules. This role is filled by certain transition metals, among them iron and copper, that have a strong tendency to bind oxygen. Multicellular organisms exploit the properties of metals, most commonly iron, for oxygen transport. However, free iron promotes the formation of highly reactive oxygen species such as hydroxyl radicals that damage DNA and other macromolecules. Iron used in cells is therefore bound in forms that sequester it and/or make it less reactive. In multicellular organisms, - especially those in which iron, in its oxygen carrying capacity, must be transported over large distances – iron is often incorporated into a protein bound prosthetic group called heme (or haeme). Heme consists of a complex organic ring structure, protoporphyrin, to which is bound a single iron atom in its ferrous (Fe+) state. The iron atom has 6 coordination bonds, 4 to nitrogen atoms that are part of the flat porphyrin ring system and two perpendicular to the porphyrin. The coordinated nitrogen atoms (which have an electron-donating character) help prevent conversion of the heme iron to the ferric (Fe3+) state. Iron in the Fe2+ state binds oxygen reversibly; in the Fe3+ state it does not bind oxygen. Heme is found in many oxygen-transporting proteins, as well as in some proteins, such as cytochromes, that participate in oxidation-reduction reactions. Free heme molecules (heme not bound to proteins) leave Fe2+ with two ‘open’ coordination bonds. Simultaneous reaction of one O2 molecule with two free heme molecules (or two free Fe2+) can result in irreversible conversion of Fe2+ to Fe3+. In heme-containing proteins, this reaction is prevented by sequestering each heme deep within the protein structure. Thus, access to the two open coordination bonds is restricted. One of these two coordination bonds is restricted. One of these two coordination bonds is occupied by a side-chain nitrogen of a His residue. The other is the binding site for molecular oxygen (O2). When oxygen binds, the electronic properties of heme iron change; this accounts for the change in colour from the dark purple of oxygen-depleted venous blood to the bright red of oxygen-rich arterial blood. Some small molecules, such as CO and NO, coordinate to heme iron with greater affinity than does O2. When a molecule of CO is bound to heme, O2 is excluded, which is why CO is highly toxic to aerobic organisms. Myoglobin Has a Single Binding Site for Oxygen: Myoglobin is a single polypeptide of 153 amino acid residues with one molecule of heme. As a typical for a globin polypeptide, myoglobin is made up of eight alpha-helical segments connected by bends. About 78% of the amino acid residues in the protein are found in these alpha helices. Protein-Ligand Interactions Can Be Described Quantitively: The function of myoglobin depends on the protein’s ability not only to bind to oxygen but also to release it when and where it is needed. In general, the reversible binding of a protein (P) to a ligand (L) can be described by a simple equilibrium expression: P + L  PL Kd = [P][L]\[PL] When [L] equals Kd, half of the ligand-binding sites are occupied. As [L] falls below Kd, progressively less of the protein has ligand bound to it. In order for 90% of the availa
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