ch339k proteins: higher order structure. higher levels of protein structure
TRANSCRIPT
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CH339K
Proteins: Higher Order Structure
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Higher Levels of Protein Structure
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Repetitive background: -N-C-C-N-C-C-
Side chains hang off the backbone
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The shape of the peptide chain can be defined by the three consecutive bond torsional angles
Bond Rotation Torsion angle definedNH to C free phiC to C=O free psiC=O to NH rigid planar omega
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Since is constrained, only and can vary
There are steric restrictions on what values they can assume
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Permissable Angles(Ramachandran Plot)
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Secondary Structures• Represent interactions among
backbone atoms
• Examples -helices Other helices -sheets - and -turns
These structures have characteristic and angles
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Pauling, Corey, and Branson (1951)
H bonds between
• carbonyl O of residue n
• amide H of residue n+4
Each amino acid is rotated 100o from the previous one.
3.6 amino acids per turn
-helix
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R/V Alpha Helix
Woods Hole Oceanographic Institute 1966-2011
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Helical parameters – Pitch and Rise
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Backbone forms helix
Side chains extend outwards ≈ -57o
≈ -47o
3.6 residues/turn
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Helix Types
-helix: C=O H-bonded to NH of residue n+4 (aka 3.613 helix)
310 helix: C=O H-bonded to NH of residue n+3 – ( ≈ -49o ≈ -26o)
-helix: C=O H-bonded to NH of residue n+5 (aka 4.116 helix)
( ≈ -57o ≈ -80o)
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Helix terminologyH-bond makes a closed loop from amide H through backbone through carbonyl ODefine helix by (a) Nbr of residues per turn (e.g. 3.6 for -helix)(b) Nbr of atoms in the loop (e.g. 13 for -helix)
NH CH C
R
O
N CH C
R
O
N CH C
R
O
N CH C
R
O
N CH C
R
O
N CH C
R
OH H H H H H
etc
3103.613
4.116 or
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Idealized Helices
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-Sheets
• Can be thought of as helix with two residues per helix
• Backbone atoms run in a plane
• Side chains extend up and down from plane
≈ -110o to -140o
≈ +110o to +135o
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C=O of residue n with N-H of residue n+3
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Gamma Turns:
C=O of residue n with N-H of residue n+2
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Angles for Secondary Structures
NOTE: Left-handed -helix has = +57, = +47
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Ramachandran Plot: Blue areas are permitted and angles
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Ramachandran plot for pyruvate kinase
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Tertiary Structures
• Three dimensional folding
• Determined by side chain interactions– Salt links– H-Bonds– Disulfides– Hydrophobic interactions
• Fibrous Proteins
• Globular Proteins
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Fibrous ProteinsKeratin
-keratin: hair, horns, and hoofs of mammals
-keratin: scales, claws and shells of reptiles, beaks and claws of birds, porcupine quills
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-keratin• Lots of Ala, Gly, Cys• All -helix (well, almost)
Right handed
Left handed
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Disulfides in the Barber Shop
Sodium thioglycolate Various peroxides
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Fibrous Proteins - Fibroin
75-80% Ala/Gly
15% Ser
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Within a fiber: crystalline regions are separated by amorphous regions.
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Fibrous Proteins - Collagen
Left handed helix of tropocollagen forms right handed triple helix of collagen.
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Hydroxyproline participates in H-bonding between tropocollagen chains
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In the absence of vitamin C, reaction 2 oxidizes Fe2+ to Fe3+.
(1)
(2)
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Lack of hydroxyls causes serious destabilization of the triple helix
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Scurvy• Weakness• Paleness• Sunken eyes• Tender gums and/or
tooth loss• Muscular pain• Reopening of old
wounds or sores• Internal bleeding• Loss of appetite• Bruising easily• Weight loss; inability
to gain weight• Diarrhea• Increased heart rate• Fever• Irritability• Aching and swelling in
joints• Shortness of breath• Fatigue
Arrrrr…
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The Brits Found the Link Between Fruits and Veggies and Healthy Sailors
Walk wide o' the Widow at Windsor, For 'alf o' Creation she owns: We 'ave bought 'er the same with the sword an' the flame, An' we've salted it down with our bones. (Poor beggars! -- it's blue with our bones!)
The Widow at Windsor – Kipling
We broke a King and we built a road --A court-house stands where the reg'ment goed.And the river's clean where the raw blood flowedWhen the Widow give the party.(Bugle: Ta--rara--ra-ra-rara!)
The Widow’s Party - Kipling
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British Empire at its Peak
• A healthy navy is a victorious navy (of course, my ancestors were less than thrilled…)
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Protein structure cartoons
-helix Antiparallel -sheet
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Globular Proteins (examples)
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Structural Motifs – “supersecondary structures”
common stable folding patternsFormed from consecutive sequencesFound in proteins w/ different functionsresult from the physics and chemistry of the structure
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Greek Key Motif (antiparallel -sheets)
a) Schematic of motifb) Staphylococcus nuclease protein
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More motifs
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Ricin B chain
• Two domains
• Each domain is a trefoil
• 3 repeats of a sheet-loop structure
• i.e. 6 repeats of a primitive fold
Domains – • Stable, independently folded, globular units• Common patterns found in different proteins• Typically have similar function• Caused by evolution (gene recombination / duplication)• Frequently (not always!) correspond to exons in genes
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C-rich Domain of Earthworm Mannose Receptor
Fibroblast Growth Factor
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Domains can be shared among proteins
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Quaternary Structure (Hemoglobin)
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Folding EnergeticsFavoring Folding Favoring Unfolding
-H from formation of intrachain H-bonds and salt links
High +S from going from folded unfolded state
+S from disulfide formation High -from making H-bonds with solvent
Enormous +S from burial of hydrophobic side chains in the interior
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Denaturation
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Denaturants
• Heat (increases negative TS contribution)
• Cold (H2O becomes less disordered)
• Pressure
• High and low pH (electrostatic effects)
• Low-polarity and non-polar solvents (e.g. EtOH)
• Chaotropes (urea, guanidinium chloride)
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• Milliseconds to seconds
• Rapid nucleation and hydrophobic collapse to “molten globule”
• Slower compaction into the native state
• Disulfides lessen negative S
• Larger proteins often have multiple structural domains
• Each domain folds by mechanisms similar to those above.
• Once folded, domains reshuffle to form the final native structure.
Protein Folding
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Effects of disulfides on folding
Denaturation of gelsolin with (open circles) and without (solid circles) 1 mM dithiothreitolFrom:Isaacson, Weeds, and Fersht (1999) Proc. Nat. Acad. Sci. 96: 11247-11252.
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Rapid 2o structure formation
Collapse to molten globule
Reshuffle to final state
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Heat Shock Proteins• Nucleotide binding domain – binds ATP and hydrolyzes it to ADP.
• Protein binding domain – contains a groove with an affinity for neutral, hydrophobic amino acid residues. The groove can interact with peptides up to seven residues in length.
• C-terminal domain –acts as a 'lid' for the substrate binding domain.
When an Hsp70 protein is ATP bound, the lid is open and peptides bind and release relatively rapidly.
When Hsp70 proteins are ADP bound, the lid is closed, and peptides are tightly bound to the protein binding domain.
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Chaperonins - GroEL
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Simpler Picture of GroEL Action
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A Problem in FoldingCreutzfeldt-Jakob Disease,
Mad Cows, and the Laughing Disease of the New Guinea Cannibals
Initially, persons may have difficulty sleeping, experience depression, problems with muscular coordination, impaired vision, and personality and behavioral changes such as impaired memory, judgment, and thinking. As the disease progresses, mental impairment becomes severe and involuntary muscle jerks (myoclonus) often occur along with blindness. Eventually, the ability to move or speak is lost and the person enters a coma until death occurs. (100% fatal)
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Prion Diseases• Human Prion Diseases
• Creutzfeldt-Jakob Disease (CJD)
• Variant Creutzfeldt-Jakob Disease (vCJD)
• Gerstmann-Straussler-Scheinker Syndrome
• Fatal Familial Insomnia
• Kuru
• Animal Prion Diseases• Bovine Spongiform Encephalopathy (BSE)
• Chronic Wasting Disease (CWD)
• Scrapie
• Transmissible mink encephalopathy
• Feline spongiform encephalopathy
• Ungulate spongiform encephalopathy
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• Kuru• Scrapie
• BSE
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Spongioform Encephalopathy – your brain on CJD
Normal Moderate Severe
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Brain atrophy in CJD – you’re usually dead before it reaches this stage
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Prion Proteins
PrPc
Normal cellular prion protein (PrPc) – mostly -helical C-terminal domain
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Prion Proteins – C terminal region
PrPc PrPsc
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Infectious Proteins
The presence of one misfolded PrPsc causes adjacent PrPc to toggle into the misfolded state.
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Various Mutations in CJD Prion Proteins
Codon Amino acid change Reference
178 aspartate to asparagine Goldfarb 1991b
180 valine to isoleucine Kitamoto 1993a
188 threonine to alanine Collins 2000
196 glutamate to lysine Peoc’h 2000
200** glutamate to lysine Goldgaber 1989
203 valine to isoleucine Peoc’h 2000
208 arginine to histidine Mastrianni 1996
210 valine to isoleucine Pocchiari 1993
211 glutamate to glutamine Peoc’h 2000
232 methionine to arginine Kitamoto 1993a
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