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Transcript
Amino Acids & Proteins Part II Dr. Kevin Ahern From Amino Acids to Proteins Peptide Bonds From Amino Acids to Proteins Peptide Bonds From Amino Acids to Proteins Peptide Bonds Alpha Carboxyl From Amino Acids to Proteins Peptide Bonds Alpha Carboxyl Alpha Amine From Amino Acids to Proteins Peptide Bonds In Ribosomes Primary Protein Structure Primary Protein Structure • Linear sequence of amino acids Primary Protein Structure • Linear sequence of amino acids • Joined by Peptide Bonds Primary Protein Structure • Linear sequence of amino acids • Joined by Peptide Bonds • Translated from mRNA using Genetic Code Primary Protein Structure • • • • Linear sequence of amino acids Joined by Peptide Bonds Translated from mRNA using Genetic Code Synthesis begins at amino end and terminates at carboxyl end Primary Protein Structure Linear sequence of amino acids Joined by Peptide Bonds Translated from mRNA using Genetic Code Synthesis begins at amino end and terminates at carboxyl end • Ultimately determines all properties of a protein • • • • Polypeptides A simple view Polypeptides A simple view Amino Terminus Carboxyl Terminus Polypeptides A simple view Free Carboxyl Group Free Alpha Amine Polypeptides A simple view Peptide Bond Peptide Bond Peptide Bond Peptide Bond Peptide Bond Polypeptides A simple view Alternating Orientations of R-groups Alternating Orientations of R-groups Peptide Bonds Chemical Character Peptide Bonds Chemical Character Double Bond Behavior Peptide Bonds Chemical Character Double Bond Behavior Alpha Carbons Usually Trans-oriented Proteins Steric Hindrance Proteins Steric Hindrance Alpha Carbons Trans Proteins Steric Hindrance Separated bulky groups Alpha Carbons Trans Separated bulky groups Proteins Alpha Carbons Trans Steric Hindrance Separated bulky groups Alpha Carbons Cis Separated bulky groups Proteins Alpha Carbons Trans Steric Hindrance Separated bulky groups Interacting Bulky Groups Alpha Carbons Cis Separated bulky groups Polypeptides Multiple Peptide Bond Planes Polypeptides Multiple Peptide Bond Planes Free Rotation Phi and Psi Angles Phi and Psi Angles Peptide Bond Peptide Bond Phi and Psi Angles Peptide Bond Phi Angle Peptide Bond Phi and Psi Angles Peptide Bond Psi Angle Phi Angle Peptide Bond Phi and Psi Angles Psi Angle Phi Angle Peptide Bond Peptide Bond Omega Angle Ramachandran Plot Bond Angles Ramachandran Plot Bond Angles Primary Angles of Stability Secondary Structure Alpha Helix Secondary Structure Alpha Helix Secondary Structure Alpha Helix Secondary Structure Alpha Helix Hydrogen bonds stabilize structure Hydrogen bonds stabilize structure Secondary Structure Beta Strands / Beta Sheets Secondary Structure Beta Strands / Beta Sheets Anti-Parallel Secondary Structure Beta Strands / Beta Sheets Anti-Parallel Parallel Secondary Structure Hydrogen Bonds Beta Strands / Beta Sheets Anti-Parallel Parallel Secondary Structure Hydrogen Bonds Beta Strands / Beta Sheets Anti-Parallel Parallel Secondary Structure Hydrogen Bonds Beta Strands / Beta Sheets Anti-Parallel Parallel Beta-‐Sheet Interactions Secondary / Supersecondary Structures Ramachandran Plot Labeled Secondary Structure Fibrous Proteins Secondary Structure Fibrous Proteins Secondary Structure Fibrous Proteins Secondary Structure Fibrous Proteins • Collagen Secondary Structure Fibrous Proteins • Collagen • Connective tissue Secondary Structure Fibrous Proteins • Collagen • Connective tissue • Keratin Secondary Structure Fibrous Proteins • Collagen • Connective tissue • Keratin • Hair / nails Secondary Structure Fibrous Proteins • Collagen • Connective tissue • Keratin • Hair / nails • Fibroin Secondary Structure Fibrous Proteins • Collagen • Connective tissue • Keratin • Hair / nails • Fibroin • Silk Collagen Partial Sequence Collagen Primary Structure Partial Sequence Collagen Primary Structure Hydroxyproline Partial Sequence Collagen Primary Structure Hydroxyproline Partial Sequence Collagen Primary Structure Hydroxyproline Proline in Helix Partial Sequence Collagen Primary Structure Hydroxyproline Proline in Helix Partial Sequence Collagen Primary Structure Hydroxyproline Proline in Helix Abundant Glycine Partial Sequence Collagen Primary Structure Hydroxyproline Proline in Helix Abundant Glycine Occasional Lysine Partial Sequence Collagen Primary Structure Hydroxyproline Proline in Helix Abundant Glycine Occasional Lysine Partial Sequence Structural Proteins Structural Proteins Keratins Structural Proteins Keratins Fibrous Structural Proteins Keratins Fibrous 50 in Humans Structural Proteins Keratins Fibrous 50 in Humans Intermediate Filaments of Cytoskeleton Structural Proteins Keratins Fibrous 50 in Humans Intermediate Filaments of Cytoskeleton Hair, nails, horns Fibroin Fibroin Silk Fibroin Silk Beta sheets Fibroin Silk Beta sheets Repeating glycines Secondary Structure Types Secondary Structure Types Alpha Helix Secondary Structure Types Alpha Helix Secondary Structure Types Alpha Helix Beta Strands / Beta Helix Secondary Structure Types Alpha Helix Beta Strands / Beta Helix Secondary Structure Types Alpha Helix Beta Strands / Beta Helix Reverse turns (5 types) Secondary Structure Types Alpha Helix Beta Strands / Beta Helix Reverse turns (5 types) Secondary Structure Types Alpha Helix Beta Strands / Beta Helix Reverse turns (5 types) 310 Helix Secondary Structure Types Alpha Helix Beta Strands / Beta Helix Reverse turns (5 types) 310 Helix Secondary Structure Tendencies of Amino Acids Secondary Structure Tendencies of Amino Acids High Propensity for Alpha Helices Secondary Structure Tendencies of Amino Acids High Propensity for Alpha Helices High Propensity for Beta Strands Secondary Structure Tendencies of Amino Acids High Propensity for Alpha Helices High Propensity for Beta Strands High Propensity for Reverse Turns Amino Acid Hydropathy Amino Acid Hydropathy Soluble vs. Membrane Bound Proteins Soluble vs. Membrane Bound Proteins Soluble vs. Membrane Bound Proteins Hydrophobic Amino Acid Bias Inside Hydrophilic Amino Acid Bias Outside Soluble vs. Membrane Bound Proteins Hydrophobic Amino Acid Bias Inside Hydrophilic Amino Acid Bias Outside Hydrophobic Amino Acid Bias In Bilayer Soluble vs. Membrane Bound Proteins Hydrophobic Amino Acid Bias Inside Hydrophilic Amino Acid Bias Outside Hydrophobic Amino Acid Bias In Bilayer Hydrophilic Amino Acid Bias Outside of Bilayer Metabolic Melody Oh Little Protein Molecule (To the tune of "Oh Little Town of Bethlehem") Copyright © Kevin Ahern Oh Little Protein Molecule (To the tune of "Oh Little Town of Bethlehem") Copyright © Kevin Ahern Oh little protein molecule You're lovely and serene With twenty zwitterions like Cysteine and alanine Your secondary structure Has pitches and repeats Arranged in alpha helices And beta pleated sheets The Ramachandran plots are Predictions made to try To tell the structures you can have For angles phi and psi And tertiary structure Gives polypeptides zing Because of magic that occurs In protein fol-ding Oh Little Protein Molecule (To the tune of "Oh Little Town of Bethlehem") Copyright © Kevin Ahern Oh little protein molecule You're lovely and serene With twenty zwitterions like Cysteine and alanine Your secondary structure Has pitches and repeats Arranged in alpha helices And beta pleated sheets The Ramachandran plots are Predictions made to try To tell the structures you can have For angles phi and psi And tertiary structure Gives polypeptides zing Because of magic that occurs In protein fol-ding Oh Little Protein Molecule (To the tune of "Oh Little Town of Bethlehem") Copyright © Kevin Ahern Oh little protein molecule You're lovely and serene With twenty zwitterions like Cysteine and alanine Your secondary structure Has pitches and repeats Arranged in alpha helices And beta pleated sheets The Ramachandran plots are Predictions made to try To tell the structures you can have For angles phi and psi And tertiary structure Gives polypeptides zing Because of magic that occurs In protein fol-ding A folded enzyme’s active And starts to catalyze When activators bind into Its allosteric sites Some other mechanisms Control the enzyme rates By regulating synthesis And placement of phosphates And all the regulation That's found inside of cells Reminds the students learning it Of pathways straight from hell So here’s how to remember The phosphate strategies They turn the GPb's to a's And GSa's to b's Reverse Turns Reverse Turns Reverse Turns Tertiary Structure Folding and Turns Tertiary Structure Folding and Turns Alpha Helices Tertiary Structure Folding and Turns Beta Strands Alpha Helices Tertiary Structure Folding and Turns Beta Strands Alpha Helices Turns Tertiary Structure Folding and Turns Beta Strands Alpha Helices Random Coil Turns Folding of a Globular Protein Folding of a Globular Protein Unfolding of a Globular Protein Unfolding of a Globular Protein Forces Stabilizing Tertiary Structure Forces Stabilizing Tertiary Structure Hydrogen Bonds Forces Stabilizing Tertiary Structure Hydrogen Bonds Figure 2.41 - Hydrogen bonding in liquid water Wikipedia Forces Stabilizing Tertiary Structure Hydrogen Bonds Forces Stabilizing Tertiary Structure Forces Stabilizing Tertiary Structure Disulfide Bonds (Covalent) Forces Stabilizing Tertiary Structure Disulfide Bonds (Covalent) Forces Stabilizing Tertiary Structure Disulfide Bonds (Covalent) Forces Stabilizing Tertiary Structure Forces Stabilizing Tertiary Structure Forces Stabilizing Tertiary Structure Forces Stabilizing Tertiary Structure Forces Stabilizing Tertiary Structure Forces Stabilizing Tertiary Structure Forces Stabilizing Tertiary Structure Denaturing/Unfolding Proteins Denaturing/Unfolding Proteins Break forces stabilizing them Denaturing/Unfolding Proteins Break forces stabilizing them Mercaptoethanol/dithiothreitol -‐ break disulfide bonds Denaturing/Unfolding Proteins Break forces stabilizing them Mercaptoethanol/dithiothreitol -‐ break disulfide bonds Detergent -‐ disrupt hydrophobic interactions Denaturing/Unfolding Proteins Break forces stabilizing them Mercaptoethanol/dithiothreitol -‐ break disulfide bonds Detergent -‐ disrupt hydrophobic interactions Heat -‐ break hydrogen bonds Denaturing/Unfolding Proteins Break forces stabilizing them Mercaptoethanol/dithiothreitol -‐ break disulfide bonds Detergent -‐ disrupt hydrophobic interactions Heat -‐ break hydrogen bonds pH -‐ change charge/alter ionic interactions Denaturing/Unfolding Proteins Break forces stabilizing them Mercaptoethanol/dithiothreitol -‐ break disulfide bonds Detergent -‐ disrupt hydrophobic interactions Heat -‐ break hydrogen bonds pH -‐ change charge/alter ionic interactions Chelators -‐ bind metal ions Denaturing/Unfolding Proteins Break forces stabilizing them Mercaptoethanol/dithiothreitol -‐ break disulfide bonds Detergent -‐ disrupt hydrophobic interactions Heat -‐ break hydrogen bonds pH -‐ change charge/alter ionic interactions Chelators -‐ bind metal ions Denaturing/Unfolding Proteins Folding of a Globular Protein Folding of a Globular Protein Energetics of Folding Protein Structural Domains Protein Structural Domains Leucine Zipper -‐ Prot.-‐Prot. and Prot.-‐DNA Protein Structural Domains Leucine Zipper -‐ Prot.-‐Prot. and Prot.-‐DNA Leucine Zipper Protein Structural Domains Leucine Zipper -‐ Prot.-‐Prot. and Prot.-‐DNA Leucine Zipper Leucine Zipper Protein Structural Domains Leucine Zipper -‐ Prot.-‐Prot. and Prot.-‐DNA Helix Turn Helix -‐ Protein-‐DNA Leucine Zipper Leucine Zipper Helix-Turn-Helix Protein Structural Domains Leucine Zipper -‐ Prot.-‐Prot. and Prot.-‐DNA Helix Turn Helix -‐ Protein-‐DNA Zinc Fingers Leucine Zipper Zinc Finger Helix-Turn-Helix Leucine Zipper Protein Structural Domains Leucine Zipper -‐ Prot.-‐Prot. and Prot.-‐DNA Helix Turn Helix -‐ Protein-‐DNA Leucine Zipper Zinc Fingers SH2 Domains -‐ Protein-‐Protein Zinc Finger Helix-Turn-Helix SH2 Domain Leucine Zipper Protein Structural Domains Leucine Zipper -‐ Prot.-‐Prot. and Prot.-‐DNA Helix Turn Helix -‐ Protein-‐DNA Leucine Zipper Zinc Fingers SH2 Domains -‐ Protein-‐Protein Pleckstrin Homology Domains -‐ Signaling (Membrane) Zinc Finger Helix-Turn-Helix Leucine Zipper SH2 Domain Pleckstrin Domains Folding Errors Folding Errors Prion Replication Model Amyloids and Disease Amyloids and Disease Amyloids - a collection of improperly folded protein aggregates found in the human body. Amyloids and Disease Amyloids - a collection of improperly folded protein aggregates found in the human body. When misfolded, they are insoluble and contribute to some twenty human diseases including important neurological ones involving prions. Amyloids and Disease Amyloids - a collection of improperly folded protein aggregates found in the human body. When misfolded, they are insoluble and contribute to some twenty human diseases including important neurological ones involving prions. Amyloid diseases include (affected protein in parentheses) - Amyloids and Disease Amyloids - a collection of improperly folded protein aggregates found in the human body. When misfolded, they are insoluble and contribute to some twenty human diseases including important neurological ones involving prions. Amyloid diseases include (affected protein in parentheses) - • Alzheimer’s disease (Amyloid β) Amyloids and Disease Amyloids - a collection of improperly folded protein aggregates found in the human body. When misfolded, they are insoluble and contribute to some twenty human diseases including important neurological ones involving prions. Amyloid diseases include (affected protein in parentheses) - • Alzheimer’s disease (Amyloid β) •Parkinson’s disease (α-synuclein) Amyloids and Disease Amyloids - a collection of improperly folded protein aggregates found in the human body. When misfolded, they are insoluble and contribute to some twenty human diseases including important neurological ones involving prions. Amyloid diseases include (affected protein in parentheses) - • Alzheimer’s disease (Amyloid β) •Parkinson’s disease (α-synuclein) •Huntington’s disease (huntingtin), Amyloids and Disease Amyloids - a collection of improperly folded protein aggregates found in the human body. When misfolded, they are insoluble and contribute to some twenty human diseases including important neurological ones involving prions. Amyloid diseases include (affected protein in parentheses) - • Alzheimer’s disease (Amyloid β) •Parkinson’s disease (α-synuclein) •Huntington’s disease (huntingtin), • Rheumatoid arthritis (serum amyloid A), Amyloids and Disease Amyloids - a collection of improperly folded protein aggregates found in the human body. When misfolded, they are insoluble and contribute to some twenty human diseases including important neurological ones involving prions. Amyloid diseases include (affected protein in parentheses) - • Alzheimer’s disease (Amyloid β) •Parkinson’s disease (α-synuclein) •Huntington’s disease (huntingtin), • Rheumatoid arthritis (serum amyloid A), •Fatal familial insomnia (PrPSc) Protein Processing Protein Processing Chaperonins -‐ Proper folding -‐ environment for hydrophobic sequences Protein Processing Chaperonins -‐ Proper folding -‐ environment for hydrophobic sequences GroEL / GroEL-GroES Protein Processing Chaperonins -‐ Proper folding -‐ environment for hydrophobic sequences GroEL / GroEL-GroES Proteasomes -‐ Degradation to oligopeptides of about 8 amino acids each Protein Processing Chaperonins -‐ Proper folding -‐ environment for hydrophobic sequences GroEL / GroEL-GroES Proteasomes -‐ Degradation to oligopeptides of about 8 amino acids each Role of Ubiquitin Role of Ubiquitin Flag for protein destruction by proteasome Role of Ubiquitin Flag for protein destruction by proteasome Role of Ubiquitin Flag for protein destruction by proteasome Intrinsically Disordered Proteins Not all proteins folded into stable structures Intrinsically Disordered Proteins (IDPs) have regions favoring disorder IDP regions tend to lack hydrophobic residues Rich in polar amino acids and proline IDPs may favor adaptation to binding another protein IDPs may favor being modified IDPs may be more involved in signaling and regulation Non-IDPs more involved in catalysis and transport Metamorphic Proteins May adopt more than one stable structure Lymphotactin - monomeric receptor. Binds heparin as dimer Protein Structure Protein Structure • Primary – Amino Acid Sequence Protein Structure • Primary – Amino Acid Sequence • Secondary / Supersecondary – Repeating Structures – short range forces Protein Structure • Primary – Amino Acid Sequence • Secondary / Supersecondary – Repeating Structures – short range forces • Tertiary – Folded structures – longer range interactions Protein Structure • Primary – Amino Acid Sequence • Secondary / Supersecondary – Repeating Structures – short range forces • Tertiary – Folded structures – longer range interactions Metabolic Melody My Old Enzymes (To the tune of "Auld Lang Syne") Copyright © Kevin Ahern Whene’er my proteins go kaput If they are past their prime. The cells will act to soon replace All of my old enzymes They know which ones to break apart Ubiquitin’s the sign A marker for pro-TE-a-somes To find the old enzymes These soon get bound and then cut up In pieces less than nine More chopping yields the single ones Building blocks from old enzymes So in a way the cell knows well Of father time it’s true Amino acids when reused Turn the old enzymes to new My Old Enzymes (To the tune of "Auld Lang Syne") Copyright © Kevin Ahern Whene’er my proteins go kaput If they are past their prime. The cells will act to soon replace All of my old enzymes They know which ones to break apart Ubiquitin’s the sign A marker for pro-TE-a-somes To find the old enzymes These soon get bound and then cut up In pieces less than nine More chopping yields the single ones Building blocks from old enzymes So in a way the cell knows well Of father time it’s true Amino acids when reused Turn the old enzymes to new
