Papers listed: Cell2. This weeks papers. Chapt 4. Protein structure and function

(1)

1

Papers listed: Cell2

• During the semester I will speak of information

from several papers.

• For many of them you will not be required to read these papers, however, you can do so for the fun of it (and it may turn out being helpful).

• Some of these papers you will be required to read. I will make sure you know which ones they are. • These papers can be found on Eres on the library

website under my name or the course name (section 2).

• The password is Cell2.

2

This weeks papers

• Stuart and Jones. (1997). Cutting complexity down to size. Nature. Vol. 386: 437 - 438.

• Roseman et al. (1996). The Chaperonin ATPase Cycle: Mechanism of allosteric switching and movements of substrate-binding domains in GroEL. Cell. Vol. 87: 241-251.

3

Chapt 4. Protein structure and function • The importance of proteins

– Major structural components of cells. – Workers of the cell.

– See Panel 4-1.

• The functions of proteins are intimately related to their structures.

4

Chapt 4. Protein structure and function • An introductory example - the

proteosome. (Stewart and Jones, 1977),

5

Chapt. 4. Protein Structure • Proteins are composed of a linear sequence of amino acids joined by a peptide bond. Fig. 4-1 6

Chapt. 4. Protein Structure • This arrangement results in a

backbone of N-CR-CO-N-CR-CO where the side groups (R) can have interesting chemistry (Fig. 4-1)

(2)

7

Fig. 4-2

Fig. 4.2 8

Chapt 4. Protein structure

• Proteins function not as linear strings but at as space filling structures.

• Therefore protein function is intimately related to protein structure.

9

• Interactions important in protein structure. – The peptide bond

• Strong, covalent bond. • Not readily reversible.

– Non-covalent bonds or interactions.

• Individually much weaker.

10

Chapt 4. Protein structure • Non-covalent

bonds or interactions.

– Ionic

Fig. 4-4

Chapt 4. Protein structure • Non-covalent bonds or interactions. – Hydrogen (between 2 peptide bonds, between a side chain and a peptide bond, between aside chain and the

backbone) Fig. 4-4

Chapt 4. Protein structure, Figure 3-26 from big Alberts

(3)

13

Chapt 4. Protein structure • Non-covalent

bonds or interactions.

– Van der Waals

Fig. 4-4b 14

Chapt 4. Protein structure • Non-covalent bonds or interactions.

– The hydrophobic interaction

Fig. 4-5

15

Chapt 4. Protein structure • The importance of non-covalent bonds or interactions Fig. 4-6 16

Chapt 4. Protein structure • Proteins function not as linear strings

but at as space filling structures. • Therefore protein function is

intimately related to protein structure.

17

Chapt 4. Protein structure • The primary structure of a protein is

the linear arrangement of amino acids connected by covalent peptide bonds.

18

• The secondary structure is one of two (or three) common patterns of short range interactions within or between the primary structure.

• In each case, the bonds involved are H bonds between the N and the O of the peptide bonds of the backbone --- side chains are not involved.

(4)

19

Chapt 4. Protein structure • The a helix

Fig. 4-10 20

Chapt 4. Protein structure • H bonds are within the chain and bond to the peptide bond of an amino acid 3.6 amino acids away. Fig. 4-10 21

Chapt 4. Protein structure • The ß sheet (Fig 4.10)

Fig. 4-10 22

Chapt 4. Protein structure • The ß sheet (Fig 5.10) – H bonds are between chains. – H bonds do not involve side groups Fig. 4-10

Chapt 4. Protein structure • There are two

types of ß sheets

Chapt 4. Protein structure • The tertiary structure is the

arrangement of secondary structure and linking regions that results in a domain or a protein monomer.

(5)

25

Fig. 4-19

26

• Bonds involved in the tertiary structure include all kinds of non-covalent bonds, H bonds of multiple types, ionic bonds, van der Waals interactions, hydrophobic interactions. Side chains are frequently involved.

27

• The quaternary structure is the arrangement of protein molecules into a larger structure.

Fig. 4-22

28

Chapt 4. Protein structure • Bonds involved include all kinds of

non-covalent bonds, H bonds of multiple types, ionic bonds, van der Waals interactions, hydrophobic interactions. Side chains are frequently involved.

29

Chapt 4. Protein structure • Similar looking proteins can be constructed very differently. Fig 4.20 30

Chapt 4. Protein structure • Proteins fold into minimum energy

conformations.

(6)

31

Chapt 4. Protein structure • The challenge of determining protein

structure. (see pgs 130-132)

– Primary structure fairly easy to determine from isolated protein.

– Primary structure is even easier to predict from the gene.

– However, much more difficult to determine how the primary structure is folded.

32

– However, much more difficult to determine how the primary structure is folded.

• Experimental:

– Crystallize the protein – Bombard with x-rays

– Interpret the diffraction pattern

• Computer analysis from primary sequence data.

– After all, folding simply is about forming the weak interactions such H bonds, ionic bonds etc.

– However it is difficult because there are a very large number of possible interactions to consider.

33

Chapt 4. Protein structure • Protein families. Fig. 4-21

34

Chapt 4. Protein structure • Development of protein families.

– Gene duplication A to A and A’

– Protein coded for by A can continue to do its job. – However gene/protein A’ can undergo mutation

and develop a new (but related) function.

• An example: globin genes.

Human

(7)

37

• Extracellular proteins are often stabilized by “disulfide bridges” (covalent cross-links) Fig. 4-29.

38

Chapt 4. Protein structure • The amino acid side chains (and to a

lesser extent the backbone),

contribute to the proteins chemistry (and thus function)

39

• Small molecules tightly bound to proteins can play important roles in the function of the proteins. Fig. 4-36

retinal heme ₄₀ Chapt 4. Prions • Infectious misfolding can cause disease • Prions – “mad-cow disease” – Creutzfeldt-Jakob disease • (Fig 4-8) 41

Other protein folding diseases • Abnormal protein folding can cause other

diseases:

– Alzheimer’s disease

• Extracellular protein aggregates

– Parkinson’s disease

• Aggregation of proteins in nerve cells.

– Huntington’s disease.

• Aggregation of proteins in nerve cells due to extra glutamine’s inserted in primary structure.

42 • Synthesis and folding of proteins – Some proteins self-assemble • The molten globule (Fig. 4-28 from big Alberts)

The birth and death of proteins

Molten globule Native (=folded) state

(8)

43

• Molecular chaperones

• History of chaperones and HSPs • Importance and mechanism

The birth and death of proteins

44

The HSP-70 family of HSPs Fig. 6-83 from big Alberts

45

The HSP-60 family of HSPs Fig. 6-84 from big Alberts

46

Alan M. Roseman, Shaoxia Chen, Helen White, Kerstin Braig, and Helen R. Saibil. 1996. The Chaperonin ATPase Cycle: Mechanism of Allosteric Switching and Movements of Substrate-Binding Domains in GroEL. Cell, Vol. 87, 241-251

• Degradation of proteins

• Why degrade proteins? • The ubiquitin dependent

pathway for protein degradation (Fig. 7-32)

– a) The proteosome. – b) Ubiquitin (the tag) – c) The overall process

(9)

49

Stewart, D. I. and E.Y. Jones. 1977. Cutting complexity down to size. Nature 386:437-438.

50 Stewart, D. I. and E.Y. Jones. 1977. Cutting complexity down to size. Nature 386:437-438. 51 Stewart, D. I. and E.Y. Jones. 1977. Cutting complexity down to size. Nature 386:437-438.