Fundamentals of Protein Structure August, 2006 Tokyo University of Science Tadashi Ando

Proteins play key roles in a living system Three examples of protein functions Catalysis: Almost all chemical reactions in a living cell are catalyzed by protein enzymes. Transport: Some proteins transports various substances, such as oxygen, ions etc. Information transfer: For example, hormones. Alcohol dehydrogenase oxidizes alcohols to aldehydes or ketones Haemoglobin carries oxygen Insulin controls the amount of sugar in the blood

Amino acid: Basic unit of protein COO- NH3+ C R H Different side chains, R, determin the properties of 20 amino acids. Amino group Carboxylic acid group An amino acid

20 Amino Acids Nonpolar, hydrophobic Polar, uncharged Polar, charged http://www.people.virginia.edu/~rjh9u/aminacid.html

Proteins are linear polymers of amino acids NH3＋ C COOー ＋ NH3＋ C COOー ＋ H H A carboxylic acid condenses with an amino group with the release of a water H2O H2O R1 R2 R3 NH3＋ C CO NH C CO NH C CO H Peptide bond H Peptide bond H The amino acid sequence is called as primary structure F T D A G S K A N G S

Amino acid sequence is encoded by DNA base sequence in a gene DNA molecule DNA base sequence ・ C G A T ＝

Amino acid sequence is encoded by DNA base sequence in a gene Second letter T C A G First letter TTT Phe TCT Ser TAT Tyr TGT Cys Third letter TTC TCC TAC TGC TTA Leu TCA TAA Stop TGA TTG TCG TAG TGG Trp CTT CCT Pro CAT His CGT Arg CTC CCC CAC CGC CTA CCA CAA Gln CGA CTG CCG CAG CGG ATT Ile ACT Thr AAT Asn AGT ATC ACC AAC AGC ATA ACA AAA Lys AGA ATG Met ACG AAG AGG GTT Val GCT Ala GAT Asp GGT Gly GTC GCC GAC GGC GTA GCA GAA Glu GGA GTG GCG GAG GGG

Basic structural units of proteins: Secondary structure α-helix β-sheet Secondary structures, α-helix and β-sheet, have regular hydrogen-bonding patterns.

Hierarchical nature of protein structure Primary structure (Amino acid sequence) ↓ Secondary structure （α-helix, β-sheet） Tertiary structure （Three-dimensional structure formed by assembly of secondary structures） Quaternary structure （Structure formed by more than one polypeptide chains）

Primary Structure Polypeptide chains  Amino Acids Largest polypeptide chain approx has 5000AA but most have less than 2000AA Arrangement of the 20 amino acids in the polypeptide is the amino acid sequence which composes the primary structure of the protein National Genome Research Institute genome.gov

Secondary Structure Secondary structures refers to the helical nature of the proteins. The secondary structure is derived from the primary structure by the formation of hydrogen bond interactions between amino acid residues fairly close to one another Secondary structure is defined by the patterns of hydrogen bonds formed between amine hydrogen and carbonyl oxygen atoms contained in the backbone peptide bonds of the protein This leads to the folding of polypeptide chain into a helix

Tertiary Protein Structure Defines the three dimensional conformation of an entire peptide chain in space Determined by the primary structure Modular in nature

Aspects which determine tertiary structure Covalent disulfide bonds from between closely aligned cysteine residues form the unique Amino Acid cystine. Nearly all of the polar, hydrophilic R groups are located in the surface, where they may interact with water The nonpolar, hydropobic R groups are usually located inside the molecule

Motifs and Domains Motif – a small structural domain that can be recognized in a variety of proteins Domain – Portion of a protein that has a tertiary structure of its own. In larger proteins each domain is connected to other domains by short flexible regions of polypeptide.

Protein Folding Protein folding constitutes the process by which a poly-peptide chain reduces its free energy by taking a secondary, tertiary, and possibly a quaternary structure

Quaternary Structure Not all proteins have a quaternary structure A composite of multiple poly-peptide chains is called an oligomer or multimeric Hemoglobin is an example of a tetramer Globular vs. Fibrous

Three-dimensional structure of proteins Tertiary structure Quaternary structure

Close relationship between protein structure and its function Example of enzyme reaction Hormone receptor Antibody substrates A enzyme enzyme B Matching the shape to A Digestion of A! enzyme A Binding to A

Functions of proteins 1. Enzyme catalysts: Almost all chemical reactions in the biological system are catalysed by enzymes. The enzymes exhibit enormous catalytic power. They increases reaction rates at least a million fold. Several thousand enzymes have been identified in the biological systems. The striking fact it that all the enzymes are proteins.

Functions of proteins 2. Transport: Proteins transport ions and small molecules across the cells of organism. Haemoglobin, a conjugated protein of blood, transports oxygen. Myoglobin, a muscle protein, transports oxygen in the muscles. Transferrin carries iron in the plasma of blood. The lipoproteins of plasma carry lipids from the liver to other organs The membrane proteins transport glucose, amino acids and other nutrients across the cell membrane

Functions of proteins 3. Storage: 4. Nutrients: Certain proteins functions as a storage of molecules, Ferritin, a protein stores iron in the liver 4. Nutrients: Certain proteins functions as nutrients The egg contains ovalbumin The milk contains casein Contraction and movement: The contraction of muscle is brought about by two fibrous proteins called actin and myosin The microtubules of flagella and cilia are built on tubulin protein

Functions of proteins 6. Mechanical support: Many proteins serve as supporting filaments, cables or sheets to give biological structures, strength, support and protection. Collagen, a fibrous protein is the major component of cartilage and leather. Keratin, an insoluble protein, is the main component of hair, finger nails and feathers. Fibroin is the major component of silk fibres and spider web.

Functions of proteins 7. Immune protection: 8. Blood clotting: Proteins defends organisms against invasion by other organisms. Invading bacteria, virus, etc.. elicit the production of antibodies by lymphocytes. Antibodies neutralises the foreign germs Antibodies are proteins, immunoglobulins. 8. Blood clotting: Bleeding is stopped by the formation of clot. Clotting is brought about by blood clotting proteins such as fibrinogen and thrombin

Functions of proteins 9. Transmission of nerve impulse: Acetylcholine, a receptor protein, helps to transmit nerve impulse. 10. Hormonal action: Many hormones are proteins. Eg. Insulin, growth hormone, parathyroid hormone etc.. Gene expression: In a cell, all the genes are not functioning at a time. Only few genes are active and the other genes remain in an inactive condition. The inactivation of genes is brought by repressor protein.

Summary Proteins are key players in our living systems. Proteins are polymers consisting of 20 kinds of amino acids. Each protein folds into a unique three-dimensional structure defined by its amino acid sequence. Protein structure has a hierarchical nature. Protein structure is closely related to its function. Protein structure prediction is a grand challenge of computational biology.