The structural organization within proteins Kevin Slep June 13 th , 2012
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The structural organization within proteins
Kevin SlepJune 13th, 2012
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From Linear Peptide to a 3D Fold1951
Herman Branson Linus PaulingRobert Corey
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The Amino AcidThe Building Blocks of Proteins
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The 20 Amino AcidsThe Building Blocks of Proteins
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The Peptide Chain, Primary StructureAssembled by the Ribosome During Translation
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Peptide Backbone: Phi Psi AnglesLimits to their distribution
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Ramachandran PlotEnergy limits to the Phi Psi Distribution
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The Globular Protein FoldExterior: HydrophillicInterior: Hydrophobic
Soluble Proteins:
How would the organization of a Membrane Protein compare?
L
A
G
SV
E
T
R
K
D
I
P
N
Q
F
YM
H
CW
PackingCross Section of a Globular Protein
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Interactions That Stabilize Protein Folds
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Secondary StructureHelicesStrands
and Loops
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First: How do we determine structure?
Our Tools:Solution NMR
Nuclear Magnetic Resonance
Distance ConstraintsDynamic Snapshot
X-ray Crystallography
Electron DensityStatic Snapshot
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Secondary Structure: The -Helix
3.6 residues per turn
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Secondary Structure: The -Helix
Helical Axis
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Secondary Structure: The -HelixHelical Wheel – Hydropathy Plots
Helical Axis
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Forms of Helices
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Secondary Structure:The -Sheet: Parallel-Strands
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Secondary Structure:The -Sheet: Parallel-Strands
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Secondary Structure:The -Sheet: Anti-Parallel -Strands
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Secondary Structure: LoopsLinkers, Variable Structrure, Active Site
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Cystine: The Disulfide BondTwo Cysteines Covalently Bond (Oxidation)
Provides Added Stabilization to a Fold
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Secondary Structure Prediction ToolsOnline Sites:
Predict Protein http://www.predictprotein.org/
Phyre http://www.sbg.bio.ic.ac.uk/phyre/
Jpred3 http://www.compbio.dundee.ac.uk/~www-jpred/
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Secondary Structure:
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Structure is Conferred by Main Chain Conformation and
Side Chain Conformation – PackingRotamers:
Favored Geometries/Energy States
Phenylalanine
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How Secondary Structure is Organized:
Motifs and Tertiary Structure
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Topology Diagrams
Jane Richardson (Duke Univ.)
Triose Phosphate Isomerase
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Structural Motifs Hairpin
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Structural MotifsHelix-Loop-Helix
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Structural MotifsEF-Hand
Calmodulin: 4 EF Hands
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Structural MotifsZinc_Finger
Two Histidines on a HelixTwo Cysteines on a Loop
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Structural MotifsGreek Key
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Structural MotifsGreek Key
Pre-albumin
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Structural MotifsJelly Roll
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Structural Motifs
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Structural MotifsRossmann Fold
Nucleotide Binding
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Helix-Turn-HelixDNA Binding Proteins
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Four-Helix Bundle
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Catalytic Triad
Aspartate, Histidine, Serine
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TIM Barrel Domain
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-Barrel
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-Propeller Domain
Neuraminidase
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Non-Protein Molecules That Play a Role in Structure and Function
The Heme Group in Hemoglobin
Cofactors
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Non-Protein Molecules That Play a Role in Structure and Function
Water in PrealbuminFirst Hydration Shell
Ordered Water
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Non-Protein Molecules That Play a Role in Structure and Function
Ions
Water in Prealbumin
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How Do Proteins Fold?
Moving from a linear peptideTo a Motif
To a Domain
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Protein Folding: Energy Landscape
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Protein Folding: Pathways
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Protein Folding: Help From Chaperones
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Protein DomainsBuilt from Motifs
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Domains solenoid – a curved structure
peridinin-chlorophyll-containing protein - trimer
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Domains
WD40 protein
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Domains
Helices and StrandsAlternate in the peptide
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Domains
Saddle
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and Domains
Helices and StrandsAre separated in the peptide
DNA ClampPCNA
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Irregular Folds
Conotoxin, disulfide in yellow
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Examples of Protein Structure
Structure Confers Function
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Membrane ProteinsPorins
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Membrane ProteinsAquaporins
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Membrane ProteinsG-Protein Coupled Receptors
GPCR: Rhodopsin
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Membrane ProteinsIon Channels
Potassium Channel
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Viral ProteinsReovirus Core
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Immunoglobulins
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Signaling Molecules: G-protiens
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Structural ProteinsClathrin
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Structural ProteinsActin Filaments: Actinh
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Structural ProteinsMicrotubules: Tubulin
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Motor ProteinsKinesin
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Motor ProteinsMyosin
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Protein Folds – as of 200810562008
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Various Folds Confer Dynamic Properties
T4 Lysozyme
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Various Folds Confer Dynamic Properties
G-proteinsNucleotide-dependent Conformational change
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Quaternary Structure
Oligomerization of the same protein, or multiple different proteins
Homodimer Heterodimer
Homotrimer Heterotrimer
Homotetramer Heterotetramer
The Coiled Coil
A common dimerizationmotif
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Quaternary Structure
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Quaternary Structure-globin E6V Mutation: Sickle Cell Anemia
Sickle Cell MalariaHeterozygotes are protected from malaria
PaulingHemoglobin is responsible
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PyMol Demonstration
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Discussion QuestionsOpen discussion on the PNAS paper by Pauling, Corey and Branson
What is the importance of tertiary structure for an active site?
Why is it important to study secondary and tertiary structure?
How important is it to know structure and what does structure tell us about function?
Can you predict the tertiary structure from primary or secondary structure.
Can you predict the quaternary structure from primary, secondary or tertiary Structure?
Why are some protein folds seen over and over again in nature – and used for different functions.