Protein structural organisation

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PROTEIN STRUCTURAL ORGANIZATION

• M.Prasad Naidu
• MSc Medical Biochemistry,
• Ph.D.Research Scholar

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Our life is maintained by molecular network
systems
Molecular network system in a cell
(From ExPASy Biochemical Pathways
http//www.expasy.org/cgi-bin/show_thumbnails.pl?2
)
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Proteins play key roles in a living system

• Three examples of protein functions
• CatalysisAlmost all chemical reactions in a
  living cell are catalyzed by protein enzymes.
• TransportSome proteins transports various
  substances, such as oxygen, ions, and so on.
• Information transferFor example, hormones.

Alcohol dehydrogenase oxidizes alcohols to
aldehydes or ketones
Haemoglobin carries oxygen
Insulin controls the amount of sugar in the blood
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Biology/Chemistry of Protein Structure

• Primary
• Secondary
• Tertiary
• Quaternary

Assembly Folding Packing Interaction
S T R U C T U R E
P R O C E S S
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Primary structure

• 1.Primary structure denotes the number and
  sequence of aminoacids in the peptide chain and
  location of disulfide bonds,if present
• 2.The higher levels of organisation are decided
  by the primary structure.
• 3.The primary structure is maintained by the
  covalent peptide bond.
• 4.peptide bonds are not broken down by conditions
  that denature proteins,such as heating or high
  concentrations of urea.

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• 5.Peptide bonds need prolonged exposure to a
  strong acid or base at elevated temperatures to
  hydralyse non enzymatically.
  
  

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CHARECTERSTICS OF PEPTIDE BOND

• 1.Partial double bond.It is rigid and planar.so
  there is no freedom of rotation.
• 2.The C-N bond is trans in nature because of
  steric interference of the R-groups when in the
  cis position.
• 3.the distance is 1.32Awhich is midway between
  single bond(1.49A) and double bond (1.27 A)
• 4.The side chains are free to rotate on either
  side of peptide bond.

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• 5.The angles of rotation known as Ramchandran
  angles,determines the spatial orientation of
  peptide chain.

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NUMBERING OF AMINOACIDS

• PSEUDOPEPTIDE
• Eg Glutathione (gamma glutamyl-cysteinyl-glycine)
  
• FORMATION OF PEPTIDE BOND
• Nameing of aminoacids in a polypeptidechain
• By changing the suffix in to yl
• Eg NH2-Gly-Ala-Val-COOH
• glycyl-alanyl-valine

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BRANCHED AND CIRCULAR PROTEINS

• Generally ,primary structure is linear.
• Branched proteins are produced by interchain
  disulfide bond
• Eginsulin
• Circular protein Eg Gramicidin.

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Clinical significance

• A single aminoacid change (mutation) in the
  linear sequence may have profound biological
  effects on the function.
• Eg
• Sickle cell anemia
• HbS is produced by substitution of Valine in
  place of Glutamic acid in the 6th position of
  beta chain of HbA.

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Secondary structure

• Secondary structure denotes the configurational
  relationship between residues which are about 3-4
  aminoacids apart in the linear sequence.
• It is maintained by Hydrogen bonds,
• 
  Electrostatic bonds,
• 
  Hydrophobic bonds,
• Van der
  waals forces.

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1.Alpha helix

• 1.Alpha helix is a spiral structure.Polypeptide
  bonds form the back-bone core and the side chains
  of aminoacids extend outward to avoid interfering
  sterically with each other.
• 2.It is the most common and stable conformation
  for a polypeptide chain.
• abundent in hemoglobin and
  myoglobin ---- globular and flexible molecule.
• absent in chymotrypsin.

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• 3.Present in keratins,fibrous proteins ------
  major component of hair and skin--- rigidity is
  determined by number of disulfide bonds in it.

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• 4.The structure is stabilized by hydrogen bonds
  between NH and CO groups of the main chain.
• 5.Each turn is formed by3.6 residues.the distance
  between each aminoacid residue is 1.5 A.
• 6.It is generally right handed because aminoacids
  found in proteins are of L-variety,which exclude
  left handedness.

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Aminoacids that disrupts an alpha-helix

• 1.Proline and Hydroxy proline will not allow the
  formation of alpha-helix because
• a) its secondary aminogroup is not
  geometrically copatible with the right handed
  spiral of alpha-helix.
• b)it inserts a kink in the chain,which
  interfers with the smooth,helical structure.
• 2.Large number of charged aminoacids also disrupt
  by forming ionic bonds or by electrostatically
  repelling each other.

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• 3.aminoacids with bulky side chains ,such as
  tryptophan,valine,isoleucine,that branch at beta
  carbon,if present in large numbers---- also
  interferes.

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• 2.Beta pleated sheet
• 1.the surfaces of beta-sheets appear pleated
  ----beta pleated sheets.
• 2.it is formed by the polypeptide chain folding
  back on itself.
• 3.The polypeptide chains are fully extended.The
  distance between adjacent aminoacids is 3.5 A.
• 4.It is stabilized by hydrogen bonds between NH
  and CO groups of neighboring polypeptide
  segments.
• 5.Strands run in same direction regard to the
  amino and carboxy terminal ends of poly peptide
  chain--------------- parallel.
• Eg Flavodoxin

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• 6.Strands run in opposite direction
  --------------- antiparallel
• Eg Silk fibroin
• 7.Both are present in Carbonic anhydrase.
• 3.Beta bends(reverse turns,Beta-turns)
• 1. are formed by the abrupt U-turn folding of
  chain.Intrachain disulfide bridges stabilize
  these bends.
• 2.it reverse the direction of a polypeptide chain
  to form a copact,globular shape.
• 3.they are usually present on the surface of
  protein molecules.
• 4. it usually composed of 4 aminoacids,among one
  is
• Proline -----causes kink
• Glycine ----smallest

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4.Non repetitive secondary structure

• 1.small part of polypeptide chain forms loop or
  coil.
• 2. it is less regular structure than alpha helix
  and beta pleated sheets.
• 5.SUPER SECONDARY STRUCTURE(MOTIFS)
• Produced by packing side chains from adjascent
  secondary structural elements close to each
  other.

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• Eg Zinc finger motif common .found in
  transcription factors.
• COLLAGEN
• It is a triple helix.
• Formed by mainly
• Proline kinks because of its ring structure
• Glycine- fits in to the restricted spaces where
  the three chains of the helix come together.

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3.TERTIARY STRUCTURE

• 1.Tertiary structure denotes three dimensional
  structure of whole protein.
• 2.It defines steric relationship of aminoacids
  which are far apart from each other in linear
  sequence,but are close in three-dimensional
  aspect.
• 3.It is thermodynamically most stable.
• 4.it refers to folding of domains and to the
  final arrangement of domains in the polypeptide.

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• 4. It is maintained by Hydrogen bonds,
• 
  Electrostatic bonds,
• 
  Hydrophobic bonds,
• Van der
  waals forces.
• 1.DOMAINS
• 1.These are fundamental functional and three
  dimensional structural units of polypeptides.
• 2.The core of domain is built from combinations
  of super secondary structural elements (motifs).
• 5.Domain is a compact globular unit of
  protein.These are connected with relatively
  flexible areas of protein.
• Eg Phenyl alanine hydroxylase enzyme contains 3
  domains,one regulatory,one catalytic and one
  protein-protein interaction domains.

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2.Protein folding

• 1.Interactions between the side chains of
  aminoacids determine how a long polypeptide chain
  folds into intricate three-dimensional shape of
  the functionalprotein.
• 2.interactions involving hydrogen
  bonds,hydrophobic bonds and disulfide bonds all
  exert an influence on the folding process.
• 3.ROLE OF CHAPERONS IN PROTEIN FOLDING

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• 1.CHAPERONES are required for proper folding of
  many species of proteins.
• 2.chaperones-also known as heat shockproteins-
  interact with the polypeptide at various stages
  during the folding process.

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4.QUATERNARY STRUCTURE

• 1.It denotes polypeptide subunits aggregate to
  form one functional unit. .
• 2.It is maintained by Hydrogen bonds,
• 
  Electrostatic bonds,
• 
  Hydrophobic bonds,
• Van der
  waals forces.

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• 3.Depending on the number of polypeptide
  chains,protein is termed as
• 1.monomer,
• 2.dimer, Egcreatine kinase
• 3.tetramer.
• Eg1.Hemoglobin,
• 2. Immunoglobulin.

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PROTEIN MISFOLDING

• 1.protein folding is trail and error process that
  can sometimes result in improperly folded
  molecules.
• 2.misfolded proteins are usually tagged and
  degraded with in the cell.
• 3.if they accumulate causes diseases.
• Eg
• 1.Amyloidoses

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• Seen in Alzeimers disease
• It is a neuro degenerative disease charecterised
  mainly by cognitive impairment.

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B.PRION DISEASE

• 1.PRION PROTEIN IS A CAUSATIVE of transmissible
  spongiform encephalopathies,
• Creutzfeldt-jakob disease in humans,
• Scrapie in sheep,
• Bovine spongiform encephalopathy in cattle.

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Summary

• Proteins are key players in our living systems.
• Proteins are polymers consisting of 20 kinds of
  amino acids.
• Each protein folds into a unique
  three-dimensional structure defined by its amino
  acid sequence.
• Protein structure has a hierarchical nature.
• Protein structure is closely related to its
  function.
• Protein structure prediction is a grand challenge
  of computational biology.