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Learn about the functions of proteins, different protein structures, folding and misfolding, and the role of proteins in human nutrition.
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Learning Objectives • To understand: • The functions of protein as an important biomolecule • Different structures of proteins • Structures of two peptide chains conformations: alpha helix and beta pleated sheet • The concept of folding, unfolding and misfolding of protein • The deficiency and excess of proteins in human nutrition
Introduction... • Proteins are the most important macromolecules in living cells. The word protein is derived from the Greek protos, meaning ‘first’ or ‘foremost’ • Almost everything that occurs in the cell involves one or more protein • Amino acids are the building blocks of proteins
Introduction • In a protein molecule many peptide chains join together to form a polypeptide chain • Proteins performs many functions in living organism • Proteins may be classified according to their physiologic functions
Classifications of proteins Nutritional quality Physiological functions - Complete - Enzymes - Partially Complete - Nutrient and Storage proteins - Incomplete OR - Contractile or Motile proteins - Protein of high BV - Structural proteins - Supplementary - Defense proteins - Protein of low BV - Regulatory proteins - Transport proteins - Other proteins
Functions of proteins… • Enzymes: The most valid and the most highly specialized proteins are those with catalytic activity – the enzymes. All the chemical reactions of organic biomolecules in cells are catalyzed by enzymes. • Transport proteins: These proteins in blood bind and carry specific molecules or ions from one organ to another, e.g. Hemoglobin, lipoprotein • Nutrient and storage proteins: The seeds of manyplantsstore nutrient proteins required for the growth of germinating seedling, e.g. seed protein of corn, rice and wheat. Ovalbumin, the protein of egg white and casein the protein of milk are other examples of nutrient proteins. The ferritin found in some bacteria and in plant and animal tissues stores iron.
Functions of proteins… • Contractile or motile proteins: Some proteins endow cells and organisms with the ability to contract, change shape, or move about. Actin and myosin function in the contractile system of skeletal muscle and in many other cells. • Structural proteins: Many proteins serve as supporting filaments, cables, or sheets to give biological structures, strength or protections. The major component of tendons and cartilage is the fibrous protein of collagen, which has very high tensile strength. Leather is almost pure collagen. Hairs, fingernails and feathers consist of the tough, insoluble protein keratin. The major component of silk fibers and spider webs is fibroin. • Defense proteins: Many proteins defend organism against invasion by other species or protect them from injury. The immunoglobulins or antibodies, the specialized proteins made by the lymphocytes of vertebrates can recognize and precipitate or neutralize invading bacteria, viruses or foreign proteins of another species. Fibrinogen and thrombin are blood-clotting factors that prevent loss of blood when the vascular system is injured.
Functions of proteins Regulatory proteins: Some proteins help regulate cellular or physiological activities, e.g. Insulin, a hormone regulates the metabolism of sugars. Other regulatory proteins bind to DNA and regulates the biosynthesis of enzymes and RNA molecules, involved in cell division in both prokaryotes and eucaryotes. Other proteins: There are numerous other proteins whose functions are rather exotic and not easily classified, e.g., monellin, a protein of an African Plant, has an intensely sweet taste. It is being studied as a nontoxic food sweetener for human use All these proteins with their very different properties and functions are made from the same group of 20 amino acids.
Properties of proteins • Proteins are very large molecules • Proteins have characteristics amino acid composition • Some proteins contain chemical groups other than amino acids • Protein can be separated and purified • Individual proteins can be quantified • The functions of a protein depend on its amino acids sequence • The amino acid sequence of polypeptides chain can be determined • Homologous proteins from different species have homologous sequences
Structures of proteins • Simple proteins are made up of peptide bond • Conjugated proteins have structures which incorporate non protein portions calledprosthetic group • The peptide chains of a particular protein molecule are folded in the same way. This is known aschain conformation • The unique chain conformation of a given protein is influenced by many week forces (disulfide bridges, ionic bond, hydrogen bond,etc.)
Levels of protein structure… Primary Secondary Tertiary Quaternary
Primary structure • Amino acid sequence of polypeptide chain • Some consider that primary structure also includes number and location of any disulphide bonds
Secondary structure… • Refers to regular recurring arrangements in space of adjacent amino acid residues in a polypeptide chain. • Most common types of secondary structures: a-helix and b-pleated sheet
Secondary structures… In someproteins, the regions of peptide chains are coiled into a spiral shape called an -Helix • -Helix is a right-handed helix. The helixes are joined together by intra-chain H-bonds formed between the carbonyl oxygen of one amino acid residue and the N-H hydrogen of the fourth residue down the chain. • R-groups protrude outward from helical backbone • Core of the helix is tightly packed
Secondary structures… b-pleated sheet consists of peptide chains arranged side by side which resembles a piece of paper folded into many pleats • Like a helix, the b-sheet uses the full H-bonding capacity of the polypeptide backbone • HOWEVER, H-bonding occurs BETWEEN neighboring peptide chains, rather than within one. • R-groups extend above and below the plane of the sheet
Secondary structures… • Helices and sheets can be combined in various ways • Some proteins have mainly a-helices, some have mainly b-sheets, but most have both
Secondary structure: fibrous proteins • Water insoluble • Usually physically tough • Usually static: provides mechanical support to individual cells and entire organisms • E.g., collagen, keratin
Examples of secondary structure The collagen triple helix. Left-handed polypetide helices are twisted together to form a right-handed superhelical structure.
Tertiary structure • Refers to the complete three dimensional structure of entire polypeptide. Usually involves the packing of structural elements (a-helix, b-pleated sheet, etc.)
Tertiary structure: globular proteins • Structurally complex • Usually dynamic • Usually compact (tightly folded), roughly spherical • Can be water-soluble • If so, characteristically have hydrophobic interior and hydrophilic surface • Can be water-insoluble (e.g., bound to biological membrane)
Examples of Tertiary structure… sperm whale myoglobin
Quaternary structure • Spatial arrangement of subunits (different polypeptide chains) within the proteins • Subunits generally associate through non-covalent interactions and, in some cases, disulphide bonds
Quaternary structure of proteins Nitritite reductase E. Coli fumarase Human hemoglobin Bacterial methane hydroxylase
Folding, unfolding and misfolding of protein • A protein that is folded into its normal physiologically active chain conformation is in its native state. • Denaturation occurs when a native protein unfolds owing to cleavage of disulfide bridges or disruption of the weak attractive forces. It may be reversible or irreversible. • Protein can be denatured by heat, extremes of pH, certain organic solvents such as alcohol, acetone, certain solute like urea, or by exposure of the protein to detergents.
Protein misfolding and diseases • There are at least 15 human diseases in which amyloid fibers accumulate (as a result of misfolding of proteins). • Amyloid diseases result in a variety of different clinical presentations, including Alzheimer’s disease. • All the proteins involve in these diseases undergo conformational alteration to a common structure in the amyloid fibril.
Importance of structure: one example of protein misfolding • Prion diseases • “misfolded” protein appears to be causative agent of many rare degenerative brain diseases in mammals
Prions… • Stanley Prusiner was awarded the 1997 Nobel Prize in Physiology or Medicine for his work on “prions” • Prion: name derived from proteinaceous and infectious • current definition: proteinaceous infectious particle that lacks nucleic acid • Prion diseases are invariably fatal neurodegenerative diseases, including bovine spongiform encephalopathy (BSE), scrapie of sheep, and Creutzfeldt-Jakob disease (CJD) of humans.
Structures of prion proteins Taken from: Prusiner, 1998. Proc Natl. Acad. Sci. USA 95:13363-13383.
Prion diseases… • May be present as genetic, infectious, or sporadic disorders • All involved modification of the prion protein (PrP) • Prions are transmissible particles, devoid of nucleic acid, and apparently composed exclusively of a modified protein.
Prion diseases • The normal cellular PrP (PrPC) is converted to modified protein through a posttranslational process during which it acquires a high b-sheet content. • Normal soluble form thus converted to insoluble form.
Stained section of the cerebral cortex from a patient with Creutzfeldt-Jakob disease shows spongiform (vacuolar) denegeration
Collagen Diseases • Scurvy • Brittle bone disease
