A continued Introduction to the elementary Setup of our Immune System #3
Here comes the promised continuation on the topic of our
Immune System - focusing on structural aspects this time!
For the two previous articles see:
Immune System #1 & Immune System #2
Visualization of Immunoglobulin G (IgG) - Image Source
The following proteins are involved in our immune response:
- Immunoglobulins
- MHC
- T cell receptors
Structural resemblance suggests that these proteins do have a single common ancestor. The X-ray structure was first solved for immunoglobulin, therefore the fold
(depicted in the first image) is called the "Immunoglobulin Fold".
As shown in the next image, the basic structure consists of two identical light and heavy chains, which are linked to each other by disulfide bonds.
There are two classes of light chains (named λ and κ) with no functional difference between them and five different isotypes of heavy chains, which divide the immunoglobulins (Igs) into different functional classes: IgG, IgD, IgE, IgA, IgM
Image Source
These classes do have different effector properties in the elimination of antigens. Each class of heavy chains can combine with either of the two classes of light chains. The ones with the simplest structure are IgGs, which are also the major class of human immunoglobulins.
A sequence comparison of IgGs shows that the N-terminal domain of each of the polypeptides contributing to the overall structure is highly variable whereas the other domain towards the C-terminus remains constant.
Hence a light chain comprises one variable domain (VL) and one constant domain (CL) though the heavy chain contains one variable domain (VH) and three constant domains (CH1, CH2, CH3). → see images
The variable domains are not uniformly variable but contain three areas of hypervariability, also called the "Complementarity Determining Regions" or short CDR1-3. These are the regions that determine the specificity of the antigen-antibody interaction.
Due to the conformational flexibility of the hinge region in the heavy chain, crystallisation of an entire Ig proved impossible. Digestion with papain, which cleaves the heavy chain in the hinge region, generates two fragments:
- Fab (Fragment, antigen binding)
- Fc (Fragment, crystallizes easily)
Thus it was possible to obtain further structural information on immunoglobulins:
The Immunoglobulin Fold
All constant domains consist of seven β- strands arranged in two anti-parallel sheets (blue and green). The sheets are closely packed against each other, are linked by a disulfide bridge between strand F in the three-stranded sheet and strand B in the four-stranded sheet and their overall arrangment can be described as a Greek Key Barrel - motif.
In the constant domains the loops are short and their sequence is invariant, latter also applies for the residues in the β-sheets (arrows).
Comparison to the variable domain
The overall structure of the variable domain is similar to the constant domain. There are only a few differences: Two additional strands are inserted into the loop region connecting strand C and D, hence there are nine instead of seven ß-strands. These two additional strands are important since they provide the hypervariable region CDR2. Two of the other loops are elongated and present the hypervariable regions CDR1 and CDR3. All three loops involved in the antigen recognition and binding are clustered together at one end of the β-sheets.
The variable domains of Igs are an excellent example of the principle that functional residues are frequently provided by loop regions attached to a stable structural framework.
The variable domain of the light (VL) and heavy (VH) chain associate with each other, giving all hypervariable regions close together at one end of the immunoglobulin. Likewise, CL and CH1 form tight and extensive contacts providing structural stability for the overall system. The constant domains associate mainly by hydrophobic interactions between the four-stranded ß-sheets in both CL and CH1.
. . .
The two variable domains are associated with each other in a strikingly different mode. If they were packed as the constant domains, the hypervariable areas would be to far away to generate an antigen binding site. In the variable domain, the two 5-stranded β-sheets form the domain-domain interaction area like shown in the following illustration:
The 5-stranded β-sheets have a curvature which results in the formation of a half-barrel. The two sheets associate such that they form a barrel structure of eight β-strands (as shown above) with the hypervariable regions at one end of the barrel structure.
Depending on the antigen, the six hypervariable loops of the two variable chains can create either flat surfaces (for binding of a large protein surface, an "epitope") or they
can generate deep crevices to bind a small molecule, a "hapten".
I hope you enjoyed this article! Follow me for more interesting scientific insights!
Best,
mountain.phil28
References:
Information and non-direct-cited images are taken from
"Molecular Physiology" lectures at the TU Graz.
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<needs WAY more coffee before she can 'look'into this :P bb ;) oh AND sugger lol
Hahahaha that may be helpful :-) maybe i should do a post about the importance of sugar in our "thinking"-process. ;-)
Best,
mountain.phil28
hm yeah && tag me :P <sitting with sugger so low the flipping messurer cant read it LOL
<is more daft then few ^^
FOUND IT!!! ha ha :P ok i wish for some legencyy now ok?? remember, no snozyyy :p and i AM blond ^^ LOL
ok im not serten i agree here>> 'Immunoglobulin Fold".
As shown in the next image, the basic structure consists of two identical ' they aint identical! are they???The basic structural unit of an antibody molecule consists of four polypeptide ... It is composed of four polypeptide chains, or?
2> i dont get the the six hypervariable loops?? were did they come from :p ? i thought 5-stranded β- was the one who changed depending on antigen? dang your smart..me no love LOL :P <side note Fun fact or what!! remember i sent music on our japp on my post? NOW as im prossesing NEW info, here is DEAD quiet LOL cool right ;)
Yes there are four polypeptide chains, but those can be divided in two light/short and two heavy/large ones. - Just for understanding. :)
You almost got it. The domain with the 5-stranded ß-sheets changes depending on the particular antigen, that shall be expressed. Nonetheless they are not randomly changed, but at the sites of the hypervariability regions, of which 3 can be found per 5-stranded ß-sheets. As two of those sheets associate to form one barrel, you will have 6 of those hypervariable loops.
I hope I could help. :)
crap!!! i soo hate feeling stupied LOL <needs to learn that lesson to :p LOL
Everyone does. :D Stay calm my lovely dragon. :D
heay obviously my brain is CALM or i would have gotten it!!! :P LOL ok i must move around a bit now before my brain totally speeds me out of control :P <dance of for a bit <la laaaa
Ok todays workout WHICH was my REST day Mr ;) LOL , is now performed BY @mountain.phil28 :P LOL Ok i can tootaly zoonk out, so im not dissing you ok??
side note , reach me at [email protected]
Hmf 'almost' is for losers :p
LOL i muust sidead a school thingi here ;) i did chemestry 1, right & huge test, and 1 of the girls was icky about it AS we needed to do public presentaion on it, soo she hade all the girls put on skirts and tight tops, so the boys wouldent pay so much attention on the wrong awnsers , <<< did obviously NOT play good & argueed the hole exam wearing jeans LOL :P
<back on track^^
aw ok sweet, THAT makes sence to me :D i wish i have hade english as native tongue :( :( O.o
Did i say, i thought they randomly changed? if so, im sorry
my 'lost6' is then actually 2 ß-sheets together, correct???
Sry, I didn't get the training-day part. :D Do you mean, I need you to write so much, so it's turning into "training"? :P
Thx. You will here from me soon. :)
oh. those boys.... :P
haha - Yes I also wish I would speak native English. :O
Ahmm. I think you didn't say this, but it looked like you didn't see where the 6 hypervariable loops came from, and yes they are coming from two ß-sheets associating together. ;)
nooo what i mean is> if you hadent japped and made me think... i would never have gotten OUT of the sofa LOL ;) I often find workout fixes/helps brain to slow down or and recharge ;)
dont you??? woow cheeses, why havent we 2 talked about that cookie before? subject needs to be talked about ha ha :D
I asked AS i never GOT that we needed 2 ß-sheets... so in my world, 6 loop, like just came up as jack in the box ^^
Yes workout is very nice for recharging your mental batteries. :) Often gives you solutions about problems which you weren't able to solve in the first place. :)
Are you sure about your E-Mail adress? My server claims that it is not existent. :D
crap ya hade me looking up & down to see wazz i hade given LOL my bad, [email protected] hm cute thow, wonder who got that email? RATFLOL shoot me now :P