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

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 ?
1 residue (e.g-Leu some times Ile) repeats after every 7 Hence called a HEPTAD. Heptad provides stong indication of CCdomain structure.

Leu packs against Leu

Original concept

Real life

(zipper)

Interactions in coiled-coil

Knobs in holes model in coiled-coil

knobs

d
a

d
e

holes

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

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

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
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

C D

E
N

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