Unit 4 Protein Structure and Function PDF

Unit 4 Protein Structure and Function Protein Structure and Function 1. Collagen 2. Elastin 3. Hemoglobin 4. Myoglobin 5. Insulin 6. Glucagon 7. Immunoglobulin Collagen: Function Most abundant protein in mammals Water-insoluble fibers Has great tensile strength...

Unit 4 Protein Structure and Function Protein Structure and Function 1. Collagen 2. Elastin 3. Hemoglobin 4. Myoglobin 5. Insulin 6. Glucagon 7. Immunoglobulin Collagen: Function Most abundant protein in mammals Water-insoluble fibers Has great tensile strength Major role: stress-bearing component of connective tissues (e.g. skin, bone, tendon, cartilage, and teeth) Collagen: Structure Primary Structure Collagen polypeptide is made up of: Repeating tripeptide sequence of X-Y-Gly (where X is any amino acid and Y is often Pro or Hydroxyproline) Lys, 5-Hydroxylysine, and His residues are present at some of the X and Y in the triplet repeat each polypeptide chain has about 1,000 amino acid residues Secondary Structure Left-handed helix and has 3.3aa/turn Gly residues found in every turn (thus permitting sharp twist of the helix) Pitch: 10 Å Collagen: Structure Tertiary Structure Three parallel polypeptide chains associate in a right-handed superhelical coiled coil structure to form a triple- helical structure (tropocollagen) The 3 chains are held together by H- bond involving hydroxyproline and hydroxylysine. Collagen: Structure Quaternary Structure Collagen fibrils are made up of tropocollagen molecules aligned in a staggered fashion and cross-linked for strength. The individual chains of triple-helical collagen molecules and the collagen molecules of fibrils are cross-linked by covalent bonds involving Lys, 5- Hydroxylysine, and His residues. With aging, cross-linking frequency increases contributing to the brittle properties of aging connective tissue. Collagen Cross-Linking Reactions Diseases due to Collagen Defects Osteogenesis imperfecta and Ehlers-Danlos syndrome are caused by mutant alleles of collagen genes. Commonly an amino acid with a relatively large R group such as Cys or Ser replaces Gly residues in mutant collagens, disrupting their structure and function. Osteogenesis imperfecta Ehlers-Danlos Syndrome ”Indian rubberman” Diseases due to Collagen Defects In the synthesis of collagen, ascorbic acid (Vitamin C) is required (as a cofactor) for the enzyme activitieds of prolyl hydroxylase and lysyl hydroxylase. These enzymes are responsible for the hydroxylation of the Pro and Lys in collagen. This leads to collagen instability and the connective tissue problems seen in the deficiency disease known as scurvy. Reaction catalyzed by prolyl hydroxylase; vitamin C maintains the enzyme in its active state. Patients with scurvy Elastin: Structure and Function Connective tissue protein with elastic properties Found in lungs, walls of large blood vessels and elastic ligaments Elastin polypeptide chain consists predominantly of nonpolar aa residues: 1/3 G, 1/3 V + A, rich in P; random coil conformation Elastin fibers associate by desmosine crosslinks (formed by 3 modified lys and 1 lys residues). Can be stretched to several times their normal length, but recoil to original shape when relaxed. Heme: Prosthetic Group in Proteins It has an ability to bind to O2. A prosthetic group (non-amino acid component required in protein function). Consists of Fe2+ bound at the center of protoporphyrin ring (4 pyrrole rings linked by methene bridges) Fe2+ has six coordination sites (4 with N of protoporphyrin, 1 with N of His, and 1 with O2) It contributes to the red color of the blood. Myoglobin (Mb): Structure and Function Made up of a single polypeptide chain (153 aa long); 8 -helices; globular protein Has a single heme group Has high O2 affinity Primary function: O2 storage protein; abundant in skeletal muscle Hemoglobin (Hb): Structure and Function Tetrameric protein: made up 2α (141 aa each) and 2β (153 aa each) subunits in a tetrahedral arrangement; each monomer is similar to Mb structure. Each subunit has 1 heme; Hb can bind up to 4 O2 molecules. Primary function: O2 transport protein Hemoglobin (Hb): Structure and Function Binds O2 reversibly and exhibit positive cooperativity (Hb’s affinity to O2 increases as more O2 is bound to it). Relative to Mb, Hb has low affinity to O2 making it more efficient O2 carrier than Mb (can easily release O2). Factors affecting Hb affinity to O2: pH Presence of CO2 Bisphosphoglycerate Oxygen Transport by Hemoglobin In actively metabolizing tissue, pH is low – decreasing Hb affinity to O2. Hb releases O2 and binds both CO2 and H+. In the lungs, pH is high – increasing Hb affinity to O2. Hb releases both CO2 and H+ and binds oxygen. Diseases due to Hemoglobin Defects SICKLE CELL ANEMIA Sickle or crescent shape RBC Substitution of Val to Glu on the 6th aa of β subunit Change in the 10 structure produce hydrophobic patch on the surface of Hb hydrophobic patch interacts with other hydrophobic patches causing the Hb to aggregate into strands that align into insoluble fibers Less efficient in delivering O2 Insulin: Structure And Function Produced from β-cells of Islets of Langerhans in the pancreas Made up of 2 polypeptide chain (51 aa); with inter- and intra- chain disulfide linkage It promotes glucose intake from blood into fat, liver and skeletal muscle cells (hypoglycemic hormone). Glucose in the cell is converted to glycogen (glycogenesis) or fats (lipogenesis). Glucagon: Structure And Function Produced from α-cells of Islets of Langerhans in the pancreas Made up of single polypeptide chain (29 aa) It elevates the blood glucose level by promoting synthesis of glucose (gluconeogenesis) and breakdown of glycogen into glucose molecules (glycogenolysis). (hyperglycemic hormone). Insulin Diseases Diabetes mellitus Type 1: failure of the pancreas to produce enough insulin Type 2: a condition in which cells fail to respond to insulin (insulin resistance) Antibody (Ab): Structure And Function Also known as immunoglobulins; secreted by the mostly by the differentiated B lympocytes (plasma cells). Ig is a glycoprotein. Y-shaped molecule consists of 2 identical Light chains (~25kDa) and 2 identical Heavy chains (~50kDa) held together by disulfide bonds. Each chain contains constant and variable regions. The variable regions in Ab serve as binding sites (paratope) to the epitope of the antigen. Antibody Isotypes Name Description Found in mucosal areas, such as the gut, respiratory tract IgA and urogenital tract, and prevents colonization by pathogens. Also found in saliva, tears, and breast milk. Functions mainly as an antigen receptor on B cells that have not IgD been exposed to antigens. It has been shown to activate basophils and mast cells to produce antimicrobial factors. Binds to allergens and triggers histamine release from mast IgE cells and basophils, and is involved in allergy. Also protects against parasitic worms. In its four forms, provides the majority of antibody-based immunity IgG against invading pathogens. The only antibody capable of crossing the placenta to give passive immunity to the fetus. Expressed on the surface of B cells (monomer) and in a secreted form (pentamer) with very high avidity. Eliminates pathogens in the IgM early stages of B cell-mediated (humoral) immunity before there is sufficient IgG. Mechanism of Antibody Can distinguish from “self” to “nonself” molecules. Ab can tag a microbe or an infected cell for attack by other parts of the immune system, or Ab can neutralize its target directly (for example, by blocking a part of a microbe that is essential for its invasion and survival). Immune Diseases Autoimmune Diseases: presence of self-reactive immune response (i.e. auto-antibodies) X-Linked Severe Combined Immune Deficiency (SCID)