Alpha-Domain Structures

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Alpha-Domain Structures
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• Alpha helices are very common in proteins.
• Could a single alpha helix exist?

Single alpha helix does not have a hydrophobic
core, it is marginally stable in solution Two (or
3,4, etc) helices can pack together and form a
hydrophobic core
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Coiled coil (leucine zipper)

• The simplest way to join two alpha helices
• In fibrous proteins (keratin, myosin) coiled-coil
  can be very long (hundreds of amino acids)
• In globular proteins coiled-coils are much
  shorter (10-30 aa)

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The heptad repeat
a b c d e f g
Met Lys Gln Leu Glu Asp Lys
Val Glu Glu Leu Leu Ser Lys
Asn Tyr His Leu Glu Asn Glu
Val Ala Arg Leu Lys Lys Leu
1 8 15 22

• d Very often Leu (hence leucine zipper)
• a often hydrophobic
• e, g often charged
• b,c,f charged or polar
• The above prefernces are strong enough to be
  predicted from sequence

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Why a heptad ?

• a helix 3.6 residues per turn
• 310 helix 3 residues per turn
• a helix in coiled coil is a bit distorted and
  has 3.5 residues per turn.
• 3.5x27, so two turns of helix form one heptad
  repeat

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Leu packs against Leu
Original concept (zipper)
Real life
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Interactions in coiled-coil
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Knobs in holes model in coiled-coil
d
d
a
a
e

• Leucines (knobs) of one helix sit in
  hydrophobic holes of other helix

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Ridges in grooves model

• Helices often pack each against other according
  to Ridges in grooves model
• NOT found in coiled coil but other motifs

Groove
Ridge
Ridge
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• Depending on actual amino acid sequence, ridges
  may be formed of residues which are 3 or 4 amino
  acids apart

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Two variants of ridges in grooves model

• If 2 helices with ridges 4 residues apart
  combine, there is 50o angle between helices
• 1 helix with ridges 4 residues apart 1 helix
  with ridges 3 residues apart ? 20o angle

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Four helix bundle

• The most usual way of packing alpha helices in
  globular proteins
• Usually ridges in grooves model

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Helices can be either parallel or anti parallel
in four helix bundle
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Two leucine zippers can form a four helix bundle

• Two helices form leucine zipper
• Two zippers pack as ridges and grooves
• Note that usually two helices in 4hb do not make
  a leu zipper, this is just a special case

Leu zipper
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Alpha-helical domains can be large and complex

• Bacterial muramidase
• (involved in cell wall formation)

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Importin beta (what a name!)
Involved in transporting (importing) proteins
from cytosol to nucleus
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Globin fold

• One of the most important a structures
• Present in many proteins with unrelated functions
  
• All organisms contain proteins with globin fold
• Evolved from a common ancestor
• Humans myoglobin hemoglobin
• Algae light capturing assembly
• Contains 8 a helices, forming a pocket for active
  site

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Myoglobin
C
C
H
F
D
B
E
G
N
A
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Hemoglobin

• Myoglobin is found in muscle cells as an internal
  oxygen storage
• Hemoglobin is packed in erythrocites and
  transports oxygen from lungs to the rest of body
• Myoglobin has a single polypeptide chain
• Hemoglobin has 4 chains of two different types
  a nd b
• Both a and b chains have a globin fold and both
  bind heme

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Hemoglobin
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Sickle-cell anemia a molecular disease

• Arises, when Glu 6 in b chains is mutated to Val

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Polymerization among hemoglobin molecules during
sickle-cell anemia

• Mutated residue 6 gets inserted in a hydrophobic
  pocket of another hemoglobin molecule

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Mutant hemoglobin fibers in erythrocytes

• Mutant Normal

Traffic jams can be caused in blood vessels by
sickle shaped erythrocites
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Why is Glu 6 mutation preserved rather than
eliminated during evolution?

• Mutation is predominantly found in Africa
• Gives protection against malaria
• Most mutation carriers are heterozygous, which
  have mild symptoms of disease, but still
  resistant to malaria an evolutionary advantage

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