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Principles of Protein Structure. primary structure. ACD EFGH I K LM NPQ RST VW Y. NH 2 Lys ine His tidine Val ine Arg inine Ala nine COOH. Different Levels of Protein Structure. Common Secondary Structure Elements. The Alpha Helix. Properties of alpha helix.

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Principles of Protein Structure

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Principles of protein structure l.jpg

Principles of Protein Structure

primary structure

ACDEFGHIKLMNPQRSTVWY


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NH2

Lysine

Histidine

Valine

Arginine

Alanine

COOH

Different Levels of Protein Structure


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Common Secondary Structure Elements

The Alpha Helix


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Properties of alpha helix

  • 3.6 residues per turn, 13 atoms between H-bond donor and acceptor

  • approx. -60º;  approx. -40º

  • H- bond between C=O of ith residue & -NH of (i+4)th residue

  • First -NH and last C=O groups at the ends of helices do not participate in H-bond

  • Ends of helices are polar, and almost always at surfaces of proteins

  • Always right- handed

  • Macro- dipole


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Alpha Helix


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Helical wheel

Residues i, i+4, i+7 occur on one face of helices, and hence show definite pattern of hydrophobicity/ hydrophilicity


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Association of helices: coiled coils

Introduction to Molecular Biophysics

These coiled coils have a heptad repeat abcdefg with nonpolar residues at

position a and d and an electrostatic interaction between residues e and g.

Isolated alpha helices are

unstable in solution but are

very stable in coiled coil

structures because of the

interactions between them

The chains in a coiled-coil have

the polypeptide chains aligned

parallel and in exact axial

register. This maximizes

coil formation between chains.

The coiled coil is a protein motif that is often used to control oligomerization.

They involve a number of alpha-helices wound around each other in a highly

organised manner, similar to the strands of a rope.


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The Leucine Zipper Coiled Coil

Introduction to Molecular Biophysics

Initially identified as a structural motif in proteins involved in eukaryotic

transcription. (Landschultz et al., Science 240: 1759-1763 (1988).

Originally identified in the liver transcription factor C/EBP which has a Leu

at every seventh position in a 28 residue segment.


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Association of helices: coiled coils

The helices do not have to run in the same direction for this type of

interaction to occur, although parallel conformation is more common.

Antiparallel conformation is very rare in trimers and unknown in

pentamers, but more common in intramolecular dimers, where the two

helices are often connected by a short loop.

Chan et al., Cell 89, Pages 263-273.


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Basis for the helical dipole

In an alpha helix all of the peptide

dipoles are oriented along the

same direction.

Consequently, the alpha helix has

a net dipole moment.

  • Since the dipole moment of a peptide bond is 3.5 Debye units, the alpha

  • helix has a net macrodipole of:

  • n X 3.5 Debye units (where n= number of residues)

  • This is equivalent to 0.5 – 0.7 unit charge at the end of the helix.

  • The amino terminus of an alpha helix is positive and the

  • carboxy terminus is negative.


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  • Structure of human TIM

  • Two helix dipoles are seen to play important roles:

  • Stabilization of inhibitor 2-PG

  • Modulation of pKa of active site His-95.


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Helical Propensities

Ala-0.77

Arg-0.68

Lys-0.65

Leu-0.62

Met-0.50

Trp-0.45

Phe-0.41

Ser-0.35

Gln-0.33

Glu-0.27

Cys-0.23

Ile-0.23

Tyr-0.17

Asp-0.15

Val-0.14

Thr-0.11

Asn-0.07

His-0.06

Gly0

Pro~3


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Common Secondary Structure Elements

The Beta Sheet


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Secondary structure: reverse turns


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Secondary Structure:Phi & Psi Angles Defined

  • Rotational constraints emerge from interactions with bulky groups (ie. side chains).

  • Phi & Psi angles define the secondary structure adopted by a protein.


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The dihedral angles at Ca atom of every residue provide polypeptides requisite conformational diversity, whereby the polypeptide chain can fold into a globular shape


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Ramachandran Plot


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Table 10

Secondary Structure


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Beyond Secondary Structure

  • Supersecondary structure (motifs): small, discrete, commonly observed aggregates of secondary structures

    • b sheet

    • helix-loop-helix

    • bab

  • Domains: independent units of structure

    • b barrel

    • four-helix bundle

  • *Domains and motifs sometimes interchanged*


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Common motifs


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Supersecondary structure:

Crossovers in b-a-b-motifs

Left handed

Right handed


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EF Hand

  • Consists of two perpendicular 10 to 12 residue alpha helices with a 12-residue loop region between

  • Form a single calcium-binding site (helix-loop-helix).

  • Calcium ions interact with residues contained within the loop region.

  • Each of the 12 residues in the loop region is important for calcium coordination.

  • In most EF-hand proteins the residue at position 12 is a glutamate. The glutamate contributes both its side-chain oxygens for calcium coordination.

Calmodulin, recoverin : Regulatory proteins

Calbindin, parvalbumin: Structural proteins


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EF Fold

Found in Calcium binding proteins such as Calmodulin


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Helix Turn Helix Motif

  • Consists of two a helices and a short extended amino acid chain between them. 

  • Carboxyl-terminal helix fits into the major groove of DNA.  

  • This motif is found in DNA-binding proteins, including l repressor, tryptophan repressor, catabolite activator protein (CAP)


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Leucine Zipper


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Rossman Fold

  • The beta-alpha-beta-alpha-beta subunit

  • Often present in nucleotide-binding proteins


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What is a Protein Fold?

  • Compact, globular folding arrangement of the polypeptide chain

  • Chain folds to optimise packing of the hydrophobic residues in the interior core of the protein


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Common folds


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Tertiary structure examples: All-a

Cytochrome Cfour-helix bundle

AlamethicinThe lone helix

Rophelix-turn-helix


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Tertiary structure examples: All-b

b sandwich

b barrel


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Tertiary structure examples: a/b

placental ribonucleaseinhibitor a/b horseshoe

triose phosphateisomerase a/b barrel


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Four helix bundle

  • 24 amino acid peptide with a hydrophobic surface

  • Assembles into 4 helix bundle through hydrophobic regions

  • Maintains solubility of membrane proteins


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Oligonucleotide Binding (OB) fold


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TIM Barrel

  • The eight-stranded a /b barrel (TIM barrel)

  • The most common tertiary fold observed in high resolution protein crystal structures

  • 10% of all known enzymes have this domain


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Zinc Finger Motif


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Domains are independently folding structural units.

Often, but not necessarily, they are contiguous on the peptide chain.

Often domain boundaries are also intron boundaries.


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Domain swapping:

Parts of a peptide chain can reach into neighboring structural elements: helices/strands in other domains or whole domains in other subunits.

Domain swapped diphteria toxin:


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Transmembrane Motifs

  • Helix bundlesLong stretches of apolar amino acidsFold into transmembrane alpha-helices“Positive-inside rule”Cell surface receptorsIon channelsActive and passive transporters

  • Beta-barrelAnti-parallel sheets rolled into cylinderOuter membrane of Gram-negative bacteriaPorins (passive, selective diffusion)


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Quaternary Structure

  • Refers to the organization of subunits in a protein with multiple subunits

  • Subunits may be identical or different

  • Subunits have a defined stoichiometry and arrangement

  • Subunits held together by weak, noncovalent interactions (hydrophobic, electrostatic)

  • Associate to form dimers, trimers, tetramers etc. (oligomer)

  • Typical Kd for two subunits: 10-8 to 10-16M (tight association)

    • Entropy loss due to association - unfavorable

    • Entropy gain due to burying of hydrophobic groups - very favourable


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Stability: reduction of surface to volume ratio

Genetic economy and efficiency

Bringing catalytic sites together

Cooperativity (allostery)

Structural and functional advantages of quaternary structure


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Quaternary structure ofmultidomain proteins


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