Download Alpha-Domain Structures

Alpha-Domain Structures
• 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
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)
The heptad repeat
a
b
c
d
e
f
g
1 Met Lys Gln Leu Glu Asp Lys
8 Val Glu Glu Leu Leu Ser Lys
15 Asn Tyr
His Leu Glu Asn Glu
22 Val Ala Arg Leu Lys Lys Leu
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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
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.
• 3.5x2=7, so two turns of helix form one
heptad repeat
Leu packs against Leu
Original concept
(“zipper”)
Real life
Interactions in coiled-coil
“Knobs in holes” model in
coiled-coil
d
a
d
a
e
• Leucines (“knobs”) of one helix sit in
hydrophobic “holes” of other helix
“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
• Depending on actual
amino acid sequence,
ridges may be formed of
residues which are 3 or 4
amino acids apart
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
Four helix bundle
• The most usual way of packing alpha
helices in globular proteins
• Usually “ridges in grooves” model
Helices can be either parallel or anti
parallel in four helix bundle
Two leucine zippers can form a
four helix bundle
Leu zipper
• 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
Alpha-helical domains can be
large and complex
• Bacterial
muramidase
(involved in cell
wall formation)
Importin beta (what a name!)
Involved in
transporting
(“importing”)
proteins from
cytosol to nucleus
Globin fold
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•
•
•
•
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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
Myoglobin
C
H
C
F
D
E
N
A
B
G
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
Hemoglobin
Sickle-cell anemia – a molecular disease
• Arises, when
Glu 6 in b
chains is
mutated to Val
Polymerization among hemoglobin
molecules during sickle-cell anemia
• Mutated residue
6 gets inserted in
a hydrophobic
pocket of
another
hemoglobin
molecule
Mutant
hemoglobin fibers
in erythrocytes
Mutant
Traffic jams
can be caused
in blood
vessels by
sickle shaped
erythrocites
Normal
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