生物化学原理课件（英文）：Chapter3 Structure and function relationships of proteins

1、Chapter 3 Structure and Function Relationships of Proteins Outline Functions of proteins Structure and function relationships of proteins General principles of structure-function relationships of proteins Several important proteins: structure- function relationships Protein function prediction Prote

2、ins are the agents of biological function C Enzymes - Ribonuclease C Signal transduction Insulin and its receptor C Control of Gene expression-Transcription factors C Immunity-Antibody C Transport and Storage - Hemoglobin C Structural proteins Hair, Collagen C Contractile proteins - Actin, Myosin C

3、Exotic proteins - Antifreeze proteins in fish C Moonlighting proteins Biological Functions of Proteins Moonlighting proteins are proteins that have secondary (hidden) functions in addition to their primary functions. Many glycolytic proteins have moonlighting activities. A special class of moonlight

4、ing proteins are trigger enzymes that control gene expression in addition to their enzymatic function. An example: Glyceraldehyde-3-phosphate dehydrogenase can double as uracil DNA glycosylase. Moonlighting proteins Function is derived from structure Structure is derived from sequence Similar sequen

5、ces have similar functions Similar function often implies evolutionary relatedness Sequence similarity suggests common evolutionary origin Many diseases are related to anomaly of some proteins -Cystic fibrosis, sickle cell anemia and mad cow disease Structure-function relationship human yeast mouse

6、plant And many other different organisms Once upon a time, there were scientists that studied Evolution and Protein Sequence Homology They believed that different organisms carried out very different biochemical reactions hmm seems like different organisms share similar biochemical processes well, s

7、eems like proteins in charge of the similar biochemical processes in different organisms are similar in many ways e.g. size, pI etc e.g. cytochrome c in respiration people were shocked when they saw the sequences of cytochrome c from different organisms But slowly and slowly they realized Comparison

8、 of cytochrome c sequences 50 amino acid difference Sequence is known in over 80 species bacteriabacteriafish similar sequences- similar structures-same function Cytochrome c 1. Found in all species that use oxygen: bacteria-humans 2. Most have 104 amino acids, 26/104 invariant 3. Evolved 1.5 billio

9、n years ago, before divergence of plants and animals 4. # amino acids differences between 2 species proportional to time of evolutionary divergence 5. Amino acid differences are not random 6. Amino acid differences survived natural selection What can be learned from amino acid sequence of cytochrome

10、 c? The number of amino acid differences between two cytochrome c sequences is proportional to the phylogenetic difference between the species from which they are derived This observation can be used to build phylogenetic trees of proteins This is the basis for studies of molecular evolution Phyloge

11、ny of Cytochrome c Phylogenetic trees of cytochrome c Analogous proteins and Homologous proteins Analogous proteins: similar or same function with different sequence, evolved from different ancestor Homologous proteins 1.Similar sequence, Similar structure, Similar function, Evolved from common ance

12、stor 2.Homolog: ortholog and paralog Homolog: ortholog and paralog Much or most of the polypeptide chain is organized approximately parallel to a single axis Fibrous proteins are often mechanically strong Fibrous proteins are usually insoluble Usually play a structural role in nature Fibrous Protein

13、s Found in hair, fingernails, claws, horns and beaks Sequence consists of 311-314 residue alpha helical rod segments capped with non-helical N- and C- termini Primary structure of helical rods consists of 7- residue repeats: (a-b-c-d-e-f-g)n, where a and d are nonpolar. Promotes association of helic

14、es! Alpha Keratin Hierarchy of alpha-keratin structure Proteins that form extensive beta sheets Found in silk fibers Alternating sequence: Gly-Ala/Ser-Gly-Ala/Ser. Since residues of a beta sheet extend alternately above and below the plane of the sheet, this places all glycines on one side and all a

15、lanines and serines on other side! This allows Glys on one sheet to mesh with Glys on an adjacent sheet (same for Ala/Sers) Beta Keratin Hierarchy of beta-keratin structure Beta-sheets found in beta-keratin Principal component of connective tissue (tendons, cartilage, bones, teeth) basic unit is tro

16、pocollagen: three intertwined polypeptide chains (1000 residues each MW = 285,000 300 nm long, 1.4 nm diameter unique amino acid composition Collagen - A Triple Helix The secrets of its a.a. composition. Nearly one residue out of three is Gly Proline content is unusually high Unusual amino acids fou

17、nd: 4-hydroxyproline 3-hydroxyproline 5-hydroxylysine Pro and HyPro together make 30% of res. Collagen The answer: Introduce extra hydrogen bond donors (-OH) to stabilize the triple helix The modifications are catalyzed by hydroxylase. The hydroylation requires O2, -ketoglutarate, and ascorbic acid

18、(vitamin C). and is activated by Fe 2+. Vitamin C helps to keep iron in the ferrous state, so its deficiency can cause Scurvy. Why has to hydroxylate Pro or Lys? A case of structure following composition The unusual amino acid composition of collagen is unsuited for alpha helices OR beta sheets But

19、it is ideally suited for the collagen triple helix: three intertwined helical strands Much more extended than alpha helix, with a rise per residue of 2.9 Angstroms 3.3 residues per turn Long stretches of Gly-Pro-Pro/HyP The Collagen Triple Helix Triple-helix conformation Gly must occupy every third

20、residue No side chains Small enough to fit inside the helix Gly aligned with X residue of one chain and Y residue of third chain Staggered arrangement in helix by one residue Mutation that causes replacement of Gly leads to defective molecules and disease Osteogenesis Imperfecta Polypeptide Chains E

21、very third residue faces the crowded center of the helix - only Gly fits here Pro and HyP suit the constraints of phi and psi Interchain H-bonds involving HyP stabilize helix Fibrils are further strengthened by intrachain lysine-lysine and interchain hydroxypyridinium crosslinks Structural basis of

22、the collagen triple helix H2NCH C (CH2)4 OH O NH3 H2NCH C (CH2)4 OH O NH3 H2NCH C (CH2)3 OH O C H O H2NCH C (CH2)3 OH O C H O H2NCH C (CH2)3 OH O CH H2NCH C (CH2)2 OH O CC O H Lysine oxidase Aldehyde derivatives aldol cross-link Collagen fibers are stabilized and strengthened by Lys-lys cross-links.

23、 Triple Helix Collagen Structures Myoglobin and hemoglobin are two of the most-studied and best-understood proteins in all of biochemistry. These are the first two proteins to have their 3D structures solved by x-ray diffraction methods, which represented a milestone in biochemistry. These proteins

24、were crucial in the conversion of anaerobic life to aerobic life. Aerobic metabolism yields much more energy than anaerobic metabolism. Allowed for more complex life forms to evolve. Problem: Oxygen has limited solubility in water. It is in fact a hydrophobic molecule. Need a way to bind oxygen effe

25、ctively, in order to deliver it to tissues in sufficient quantities. Proteins like myoglobin and hemoglobin evolved to fulfill that purpose. Myoglobin Low level of disordered protein in Mitochondria Can predict whether or not a protein will fold using this website: Fold Index Characteristics of UCPs Advantages of UCPs More malleable with respect to regulation and binding of ligands Able to bind several different ligands Have large intermolecular interfaces Overall smaller protein genome and cell sizes Some natively unfolded proteins wrap around their partner upon binding and gain a struc