Levels of protein structure, exemplified by Insulin

Click here to bring up an accompanying interactive graphics display file using Jsmol, in a separate window.


The hormone insulin is a protein consisting of 2 polypeptide chains.

Details about insulin production inside cells.

In the beta cells within islets of Langerhans of the pancreas, insulin is originally produced as a single molecule (preproinsulin) composed of 110 amino acids. After this has passed through the endoplasmic reticulum, 24 amino acids ("the signal peptide") are removed by enzyme action from one end of the chain, leaving another form (pro-insulin), which folds and bonds to give the molecule much of the final structure. This passes into vesicles budded off from the Golgi body. Here a middle section ("the C chain") of 33 amino-acids is removed by the action of the enzymes prohormone convertase 1 and 2, converting it into the final structure with 2 chains, A and B, and 2 amino acids are then removed by another enzyme carboxypeptidase E.

Primary structure (amino acid sequence) 

 Leave the mouse pointer over the 3-letter codes below for more information

A chain  (21 amino acid residues):

Amino acid 
residue number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21


      
N-terminal-->
 end(free -NH2)
GLY
ILE
VAL
GLU
GLN
CYS
CYS
THR
SER
ILE
CYS
SER
LEU
TYR
GLN
LEU
GLU
ASN
TYR
CYS
ASN
<--C-terminal
(free -COOH)

B chain  (30 amino acid residues):

Aa
no
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30


      
N
PHE
VAL
ASN
GLN
HIS
LEU
CYS
GLY
ASP
HIS
LEU
VAL
GLU
ALA
LEU
TYR
LEU
VAL
CYS
GLY
GLU
ARG
GLY
PHE
PHE
TYR
THR
PRO
LYS
THR
C

These sequences are written using standard 3-letter codes for the 20 amino acids. There is a peptide bond between each amino acid, so they are called residues because -H is removed from each intervening amino group, and -OH from the next -COOH group. At one end of each chain (the N terminal end) is an amino group, and at the other end (the C terminal end) is a carboxylic acid group. 

Insulin produced in other organisms may have a slightly different amino acid sequence, or extra amino acids, but the next levels of structure are not greatly altered by these variations.

Secondary structure (simple 3D form)

Some of the joined amino acid residues coil to form short sections of alpha helix, due to hydrogen bonds between >N-H and >C=O groups (projecting from peptide bonds of amino acids 3 or 4 residues further along), which stabilises the structure. Other amino acids give a turn to the amino acid chains so the overall structure is fairly compact.

The A chain, which is fairly compact, contains 2 sections of  alpha helix (A2 Ile - A8 Thr and A13 Leu - A19 Tyr). In between these sections is a fairly flat ribbon which enables these helices to lie alongside one another, and also brings the side chains of  A2 Ile and A19 Tyr into Van der Waals contact.

The B chain appears to wrap around the A chain. It consists of a larger section of  alpha-helix (B9 Ser - B19Cys) and the smaller  glycine residues at 20 and 23 allow it to fold into V shape. This brings the C terminal residues B24 Phe and B26 Tyr into Van der Waals contact with B15 Leu and B11 Leu of the alpha-helix. 

2 coiled polypeptide chains making up insulin
If you have Chime 2.6 installed, you can click here to bring up a 3-D display of insulin in a separate browser window. Try right-clicking to bring up a menu, then Display > Ribbons, and Color > Chain to see the view above. Options > Labels will give details about amino acid residues and numbers as above. The A chain is shown in blue, the B chain is shown in red.
Click here for a larger version of this static image.

Tertiary structure

2 insulin chains showing 3 disulphide bridges The three-dimensional structure of insulin is further stabilised by disulphide bridges. These form between thiol groups (-SH) on cysteine residues (CYS above). There are 6 cysteines, so 3 disulphide bridges are formed: 2 between the A and B chains (between A7 & B7, and A20 & B19), and one within the A chain (A6 & A11).  

In addition to this, there  are many salt bridges as well as Van der Waal's  forces mentioned above. The exterior of the molecule is mainly polar, whereas the interior is mainly non-polar.
Note the 3 disulphide bridges (yellow) above, between pairs of cysteine residues (shown as ball and socket diagrams projecting from the ribbons): One within the A chain can be seen at the top, and two between the A and B chains, are at either side. Chime 2.6 users can click here, then select Options > Display Disulfide Bridges and > Display Hydrogen Bonds to see (rather fine) dotted lines showing these bonds in the 3-D molecular structure.

Quaternary structure

Insulin can form into granules consisting of hexamers (6 insulin molecules as described above, grouped around 2 zinc ions) due to interactions between hydrophobic surfaces. This toroidal (doughnut-shaped) form is the one  in which insulin is stored in the beta cells and secreted into the blood stream.

Insulin may also form into dimers (double units).

However, the active form is a apparently a single unit (monomer).

6 insulin molecules arranged as a single hexameric unit

Chime 2.6 users can click here to see this 3-D molecular structure in a separate browser window.  To see the view above, right-click to bring up a menu, then Display > Ribbons, and Color > Chain

Key figures

Langerhans (identified different looking "islands" amongst the glandular tissue of the pancreas)

Banting and Best (performed physiological experiments on the basis of diabetes)

Dorothy Hodgkin née Crowfoot used X-ray crystallography to reveal the 3-D structure of the insulin molecule (and other important Biological molecules - Nobel prize winner 1964 for work with vitamin B12) - see link below

Sanger (worked out the primary structure of insulin, 1958 Nobel Prize winner).

Web references

http://en.wikipedia.org/wiki/Insulin

http://en.wikipedia.org/wiki/Proinsulin

Dorothy Hodgkin from Wikipedia, the free encyclopedia

Contents page         Front (index) page