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Structure-Function Relationship You have studied the amino acids and their characteristics, but in this part we will study the relation between the structure and the function of protein. Proteins can be classified according to their structure into: 1. Globular 2. Fibrous (strand like) What makes proteins take a certain structure? They take the most stable condition for them. Which means, these proteins have different structures and these structures determine the most stable condition for them, that's why some of them tend to be in globular shape and others take fibrous shape. Proteins have many functions they can work as: Enzymes--catalysts for reactions Transport molecules hemoglobin, Lipoproteins, channel proteins Contractile/motion myosin, actin Structural collagen, keratin, actin Defense antibodies Signaling hormones, receptors Toxins diphtheria, enterotoxins Structural proteins are different from other functional types; because all proteins have to move through the body to do their functions except structural proteins. Note: Proteins that can move through the body (through blood, ECF and ICF) can t move across cell membrane; because the structure of cell membrane has phospholipids which makes it hydrophobic, whereas proteins are hydrophilic. How can we make a water-soluble protein? If we have a sequence of amino acids, which is the primary structure, it will organize to form the secondary structure then tertiary. In tertiary structure, we notice that hydrophobic amino acids tend to cluster around each other by hydrophobic interactions in the center of the protein, away from water content of the body. On the other hand, the hydrophilic amino 2 P a g e
acids distribute on the surface of the protein near to the water content. So, we get a globular protein which have hydrophobic amino acids inside and hydrophilic outside. Does this mean that we can't find hydrophobic amino acids on the surface of proteins? Of course no, there are proteins with hydrophilic amino acids inside and hydrophobic outside BUT to serve a certain function, such as: interacting with other hydrophobic protein, like the interaction between the four subunits of hemoglobin, and to form the active site of the enzyme (if it was pocket like), to make a substrate catalytic reaction. If the protein is globular in shape, it has to include more than one type of secondary structure, and this makes it not packed well and having lots of spaces inside where water can get inside the protein. There s a lot of functions of globular proteins and the whole mark of these functions is that proteins have to move. So, to have a protein with a non-packed well structure, it should include more than one type of secondary structure of proteins. Example: if you have a box and you want to fill it with things without leaving any space, the best way to occupy all the spaces is to put things with similar structure (they will be tightly packed), BUT if you put things with different structures, they can't be packed well and there will be spaces in between. It 1 Conclusion: To make a globular protein the main rule is that secondary structures shouldn't be tightly packed, regardless if it's composed of one type of secondary structure or more than one (usually they are made up of more than one type of secondary structure). How to create a fibrous protein? Fibrous proteins should have one type of secondary structure that can gather up and form a tightly packed structure where water can't get inside. These tightly packed fibrous proteins (rod like) are water-insoluble, which is an important feature to give this type of proteins strength for structural purposes. 3 P a g e
Note: In the ECM, there is a meshwork composed of globular and fibrous proteins to serve their functions. Types of fibrous proteins 1. Collagen The most abundant protein in vertebrates: 25% of mammals proteins 25 different types (I, II, III, IV, etc.) Found in all multicellular animals Organized as water-insoluble fibers Has a great strength Consists of 3 polypeptide chains wrapped around each other in a rope-like twist, or triple helix (tropocollagen) Has a repeating sequence of the amino acids It exists in everywhere in the body. Its clinical relevance that it exists in the wall of blood vessels, so if we have a disease related to collagen the blood vessels start tearing and cause bleeding. Structure of collagen: Collagen has only one type of secondary structure which is α-chain (so it s tightly packed). α-chain is similar to α-helix, but the differences are: 1- α- chain is left-handed (rotates counter clockwise), while α- helix is right-handed (rotates clockwise). 2- α- chain contains 3.3 amino acids per full turn, whereas α- helix contains 3.6 amino acids per turn. This means that the chains of collagen fibers are more relaxed compared to the chains of α- helix. Collagen is composed of many monomers which are called tropocollagen. Each tropocollagen molecule composed of three α- chains twisted around each other. Each α-chain contains 800-1000 amino acids (according to the organism). Note: Each α-chain alone- is left handed, but tropocollagen is right handed. 4 P a g e
How do we create the structure of three twisted α- chains? They are tightly packed with each other due to having some features, such as containing a lot of Proline which creates kinks and helps to twist them around each other, also Proline is a rigid amino acid so it adds stiffness. Another amino acid that should be included to serve the functions is Glycine. If we look to the twisted structure we see that there are amino acids to the outside of the twists and other amino acids between twists. The amino acid that is inside the twist is glycine to allow tight packing. Note: Glycine is repeated every three amino acid in an α-chain. Suppose that the first glycine in the chain is the third amino acid, then the next glycine will be the sixth and so on. So, one third of the structure of collagen is glycine. Proline forms 13% of collagen structure and hydroxyproline forms 9%. To give collagen the strength to afford the high pressure of blood inside vessels, fibers should be cross linked with each other, and this occurs by certain amino acids which are lysine, hydroxylysine, proline and hydroxyproline. 5 P a g e
Modified amino acids: 1. After Proline is added to the chain, an enzyme called prolyl hydroxylase adds hydroxyl group to Proline and converts it to hydroxyproline. Hydroxyproline can make huge number of hydrogen bonds so it maintains the helical structure of collagen. 2. Lysyl hydroxylase add hydroxyl group to Lysine and convert it to hydroxylysine. When Lysine is oxidized and becomes (oxidized lysine), it can bind with hydroxylysine and make cross-linked covalent bonds in between different tropocollagen molecules, creating a very strong molecule. Note: These hydroxylated proteins are involved in hydrogen bonds which stabilizes the structure. Lysine Lysyl Oxidase Allysine (aldehyde form of Lysine) Hydroxylysine Lysyl Hydroxylase Hydrogen bonds VS Temperature Temperature weakens hydrogen bonds. Until 40, the helical structure of collagen is preserved. When it reaches 42-43, human dies because of the denaturation of proteins. Look at the red curve which represents the case of absence of hydroxyproline in collagen. Human loses 80% of the helical structure at about 20. 6 P a g e
To form cross linkage using Lysine and modified Lysine: 1-Hydroxylysine + Hydroxylysine 2-Hydroxylysine + Oxidized Lysine 3-Oxidized Lysine + Oxidized Lysine 4-Oxidized Lysine + non-modified Lysine 5-Hydroxylysine + non-modified Lysine They interact with each other covalently to form cross-linking between tropocollagen. Note: The amount of cross-linkage increases with age for all mammals, and this makes the protein stiffer. Prolyl Hydroxylase and Lysyl Hydroxylase need a coenzyme to function, which is Vitamin C. If there is a vitamin C deficiency, the cross-linkage will be lost. Scurvy patients have vitamin C deficiency, so their collagen is weak, and this causes spontaneous bleeding from their gum and under their skin. 2-Elastin: main constituent for elastic tissue. The structure of collagen is regular by nature, but elastin is irregular by nature (it contains short chains of α- helix but they re broken). We can imagine the structure of elastin as a wool ball that can be stretched from its pole, then it goes back to its original structure. Monomers are called tropoelastins, they form elastin and they re cross-linked. How can we make a protein with this elasticity? 1- These proteins are rich in hydrophobic amino acids to be able to aggregate with each other by hydrophobic interactions. 2- These proteins should have crossed-linking between tropoelastins, so when we apply strength on it, it can go back to its original structure. The cross-linked bonds are formed by Oxidized Lysine; because in elastic tissue there is no Lysyl Hydroxylase, it has Lysyl Oxidase only, which converts Lysine to its oxidized form. 7 P a g e
Desmosine is the structure that give strength to elastin. The structure of desmosine: It s composed of four segments, three of them give Oxidized Lysine (they don t have nitrogen), and one segment gives unmodified Lysine (contains nitrogen). The four segments aggregate around each other to form the ring structure of desmosine. When you stretch the protein, there will be a retention in this ring, and when you leave it, it comes back. Congratulations you ve finished the sheet! You deserve i8 8 P a g e