Alpha-Domain Structures

1. Alpha-Domain Structures

2. 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

3. 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)

4. The heptad repeat 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

5. 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

6. Leu packs against Leu Original concept (“zipper”) Real life

7. Interactions in coiled-coil

8. “Knobs in holes” model in coiled-coil • Leucines (“knobs”) of one helix sit in hydrophobic “holes” of other helix d d a a e

9. “Ridges in grooves model” Groove Ridge • Helices often pack each against other according to “Ridges in grooves” model • NOT found in coiled coil but other motifs Ridge

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

12. 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

14. Four helix bundle • The most usual way of packing alpha helices in globular proteins • Usually “ridges in grooves” model

15. Helices can be either parallel or anti parallel in four helix bundle

16. 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

17. Alpha-helical domains can be large and complex • Bacterial muramidase (involved in cell wall formation)

18. Importin beta (what a name!) Involved in transporting (“importing”) proteins from cytosol to nucleus

19. 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

20. Myoglobin C C H F D B E G N A

21. 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

22. Hemoglobin

23. Sickle-cell anemia – a molecular disease • Arises, when Glu 6 in b chains is mutated to Val

24. Polymerization among hemoglobin molecules during sickle-cell anemia • Mutated residue 6 gets inserted in a hydrophobic pocket of another hemoglobin molecule

25. Mutant hemoglobin fibers in erythrocytes Mutant Normal Traffic jams can be caused in blood vessels by sickle shaped erythrocites

26. 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