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 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 abcdefg MetLysGlnLeuGluAspLys ValGlu Leu SerLys AsnTyrHisLeuGluAsnGlu ValAlaArgLeuLys Leu 1 8 15 22

5. Why a heptad ?  helix: 3.6 residues per turn 3 10 helix: 3 residues per turn  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. Original concept (“zipper”) Real life Leu packs against Leu

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 a a d e

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

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

12. If 2 helices with ridges 4 residues apart combine, there is 50 o angle between helices 1 helix with ridges 4 residues apart + 1 helix with ridges 3 residues apart  20 o angle Two variants of “ridges in grooves” model

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  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  helices, forming a pocket for active site

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

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 –  nd  Both  and  chains have a globin fold and both bind heme

22. Hemoglobin

23. Sickle-cell anemia – a molecular disease Arises, when Glu 6 in  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