Protein Secondary Structure

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1958 :Kendrew Solves the Structure of Myoglobin

“Perhaps the most remarkable features of the molecule are its complexity and its lack of symmetry. The arrangement seems to be almost totally lacking in the kind of regularities which one instinctively anticipates, and is more complicated than has been predicted by any theory of protein structure”

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Protein Secondary Structure

Protein interior: Hydrophobic coreMain chain folds also into interior, but it

is highly polar

→Problem: Polar atoms must be neutralized through hydrogen bonds

→Solution: Regular secondary structure3

Helix• Discovered 1951 by Pauling• 5-40 aa long• Average: 10aa• Right handed • Oi-NHi+4 : bb atoms satisfied

• helix: i - i+5

• 310 helix: i - i+3 1.5Ǻ/res

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Helix is a Dipole

… and binds negative charges at N-term5

Side Chains project out from the Helix

View down one helical turn6

Proline Disrupts Helix

No donor!

N

CO

C H

CH2

CH2H2C

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Frequent Amino Acids at the N-terminus of helices

Pro Blocks the continuation of the helix by its side chain

Asn, SerBlock the continuation of the helix by

hydrogen bonding with the donor (NH) of N3

Ncap, N1, N2, N3 …….Ccap

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Helices of Different Character

Buried, partially exposed, and exposed

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Representation: Helical Wheel

Buried, partially exposed, and exposed

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Dihedral Angles and define Backbone Geometry

The peptide bond is planar and polar11

Ramachandran Plots

Glycine: flexible backbone

All except Glycine

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Ramachandran Plots

helix: around -60,-50, respectivelyOther defined regions: strand and loops

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Sheet

• Involves several regions in sequence• Oi-NHj

•Parallel andanti-parallelsheets

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Antiparallel Sheet

• Parallel Hbonds• Residue side chains point up/down/up ..• Pleated

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Parallel Sheet

• Less stable than antiparallel sheet• Angled hbonds

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Combined Sheet

Rare: strains in middle strand

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Examples of Sheet Topologies

Topology diagram

Closed barrel18

Connecting Elements of Secondary Structure defines

Tertiary Structure

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Loops

• Connect helices and strands• At surface of molecule• More flexible• Contain functional sites

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Hairpin Loops ( turns)

• Connect strands in antiparallel sheet

G,N,D G G S,T

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Super Secondary Structures: (1) Greek Key Motif

• 24 possible topologies for 2 hairpins• 8 found• Most common: Greek key motif

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Super Secondary Structures: (2) Motif

• Connect strands in parallel sheet

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Repeated Motif Creates -meander: TIM Barrel

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Large Polypeptide Chains Fold into Several Domains

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Protein Classification

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Protein Classification

Alpha contain only helices

Beta contain only sheets

Alpha/Beta contain combination of both

Alpha + Beta contain domains of and

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ALPHA

Occur in • Transmembrane proteins• Structural and motile proteins

• Fibrous proteins (Keratin)• Fibrinogen, myosin

• Coiled-coils (Leucine Zippers)• 4-helix-bundles• -helical domains• Globins28

ALPHA: Coiled-Coils

Francis Crick, 1953: maximal sc interactions if two helices are wound around each other

• Left-handed supercoil: 3.5 residues/turn:Heptad repeat

• “knobs-into-holes”• Leucine zipper motif in Transcription Factors (more about this later..)

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ALPHA: 4-Helix Bundle• “ridges-into-grooves”

ROP protein

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Ridges-into-Grooves2 possible arrangements:

• i-i+4 ridge:Globins

• i-i+3 ridge:ROP

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ALPHA:-Helical Domains

>20 helices form globular domainExample: muramidase

• 27 helices• right-handed superhelical twist•Hole in center

ALPHA/BETA

Most frequent3 classes:• Barrel• Twisted sheet• Horseshoe fold

• Functional sites in loop regions

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ALPHA/BETA: Barrels

• Consecutive units in same orientation

• Usually 8; 8-hb- 1

→ closed core of strands

•TIM barrelTriose Phosphate Isomerase

• Usually enzymes34

TIM Barrelsaa2,4 point out to helices• branched aas V,I,L

aa1, 3, 5 point into barrel• Bulky hydrophobic aas form tightly packed hydrophobic core

Polar aas (KRE) at tip of barrel: participate in formation of hydrophobic core35

TIM Barrels

Active site formed by loops at one end of the barrel

Distinct from structural region36

ALPHA/BETA: Open Sheet

• Consecutive units in opposite orientation: helices on both sides

• Rossman Fold (discovered in 1970 in lactate dehydrogenase)

• Many different arrangements37

Open Sheet: Functional Sites at Topological Switch Points

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ALPHA/BETA: Horseshoe Fold

• Consecutive units in same orientation

• Not closed: horseshoe

•Ribonuclease Inhibitor

• One side points to helix, • The other is exposed

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Horseshoe Fold

Leucine-rich repeats• each ~30aa• L responsible for packing

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BETA

Antiparallel structures

Usually two sheets packedagainst each other

Barrel: composed of anti-parallel strands with hairpin connectionsPropeller: multi-domain protein41

BETA Barrels

Retinol-binding protein

8 strands

Center: hydrophobic pocketbinds lipids

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BETA Propellors (I)

Neuraminidase

• 6 -sheets (each 4 strands) organized as propellor blades• Active site formed by loops from each blade

Others: G-proteins, etc43

BETA Propellors (II)

Neuraminidase

• 6 -sheets (each 4 strands) organized as propellor blades• Active site formed by loops from each blade

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BETA Propellors (III)

Neuraminidase

• 6 -sheets (each 4 strands) organized as propellor blades• Active site formed by loops from each blade

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BETA: Jelly-Roll MotifWrapped around a Barrel

Composed of repeats of greek keys

Concavalin, Hemagglutinin46

BETA: -helix Structures

Right-handed coiled structure18aa: 6 in loop + 3 in GGXGXDXUX (U=hydrophobic)Loop stabilized by Ca ionPectate lyase

Additional Useful Material

http://swissmodel.expasy.org/course/text/

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