Re: [asa] PSCF article on immune system

From: Nucacids <>
Date: Sun Dec 06 2009 - 11:10:19 EST

Hi Bill,

A protein is a chain of amino acids that folds into a particular three
dimensional conformation. A fold is a particular conformation. What
science has discovered is that even though amino acid sequence variability
is immense (for a protein of 100 amino acids there are 20^100 possible
combinations, since there are 20 different amino acids), there are only
about 1000 or so shapes/folds that are employed by life.

You can think of a fold as a region where the amino acid chain is arranged
into a scaffold. Function is tied to the scaffold when it is decorated with
an active site (which is usually some cleft or groove on the protein’s
surface that binds a substrate and converts it to a product), along with
other binding sites.

The immunoglobulin fold is a particular scaffold arrangement that is used to
make antibodies (this scaffold is also found in many other proteins). So I
am basically pondering whether there is something special about this
particular scaffold when it comes to making antibodies.

Here is a nice video that will help you visualize the immunoglobulin fold in
an antibody:

And here are a couple of essays that might help someone appreciate where I
am coming from with this:

Hope this helps,


> Mike:
> You and Craig, if you are going to expect any participation from me, and I
> suspect some others, are going to have to get down on your knees, look us
> in the eyes, and talk to us as if we are bright eyed 8 year olds.
> IOW, I don't understand a good deal of the terminology that you are both
> using.
> What, for example, is the the immunoglobulin "fold" that is so prevalent
> in
> all creation?
> Thanks for both your participation, and welcome Craig.
> bill
> On Sun, 6 Dec 2009 00:45:45 -0500, "Nucacids" <> wrote:
>> I would like to pose a question that will take people down a different,
>> less-traveled pathway. While it is clear that mutations and selection
>> play
>> key roles in the generation of antibodies, is it possible that the
>> immunoglobulin fold itself facilitates this "evolution"? In other
> words,
>> is
>> there something special about the immunoglobulin fold, such that
> mutations
>> and selection would not be nearly as successful in generating
>> antibody-function if another fold was used?
>> I ask this because the immunoglobulin fold, which is universal among all
>> domains of life, seems especially robust when it comes to tolerating
>> mutation, yet retaining the same basic 3D shape. There are proteins
> with
>> immunoglobulin folds that possess 5% sequence identity and have
> different
>> functions. In fact, so widespread is this fold that one study that
>> attempted to evaluate protein folds among the three domains had to
> exclude
>> this fold "because of the over-representation of immunoglobulin-like
>> sequences in the NR database that made the analysis of this fold very
>> computationally intensive." And to this day, people are still trying to
>> figure out whether the various immunoglobulin folds are related by
> descent
>> or keep popping into existence by convergent evolution.
>> Consider the possibility that not all protein folds are equally
>> "evolvable"
>> and that the immunoglobulin fold is rather exceptional in its
> evolvability.
>> Mike
>> ----- Original Message -----
>> From: "Craig Story" <>
>> To: <>
>> Sent: Saturday, December 05, 2009 8:34 PM
>> Subject: [asa] PSCF article on immune system
>>> There must be a way to directly reply to a thread in this listserv, but
> I
>>> just subscribed, and am happy to see people discussing my article.
>>> Let me briefly comment on two paragraphs from Bill Powers:
>>> ³It must be something like any search program. You will have to get
>>> "close" before a random search becomes useful. You might begin your
>>> search "randomly", but there must be some sort of guiding mechanism
> that
>>> quickly narrows or directs the search, e.g, gradient search.
>>> I suspect, from what Craig says, that the search is guided by a
> "memory"
>>> of previously generated antibodies, which may be why mother's milk is
> so
>>> important for the survival of children, or colostrum for the survival
> of
>>> baby goats, cows, etc.²
>>> One must keep in mind that the variety of specificities is continually
>>> generated whether or not there is an actual pathogen present. Then
>>> selection
>>> occurs as necessary. Some optimization (affinity maturation) occurs
> after
>>> ³hits² are found that bind the antigen reasonably well.
>>> Second, the memory of past useful antibodies (such as the ones that
>>> might
>>> be
>>> partially protecting some of us from H1N1 flu right now) are stored as
>>> cells
>>> that remain alive for many years. As for mother¹s milk, etc, it is the
>>> fact
>>> that the baby is in the same environment as the mother, and exposed to
>>> the
>>> same pathogens, that her useful IgA/IgM antibodies go into her milk. In
>>> the
>>> case of cows and rodents, actually it¹s IgG that is in the
>>> colostrum/milk,
>>> respectively (the topic of my PhD thesis). For humans, milk has IgM
>>> mostly,
>>> but the principle is the same. This transferred antibody is considered
>>> _passive_ immunity, since it is only protein, and has a half-life, etc.
>>> It
>>> takes some time after birth for the newborn to be able to generate its
>>> own
>>> cellular responses. In your comment it sounded a bit like you were
>>> suggesting that the transferred antibodies are somehow guiding the
> future
>>> cellular responders. That may be true to the extent that immune
> networks*
>>> are happening, but in my opinion, that is probably not be the major
>>> factor
>>> in immune repertoire development. I think of transferred Ab as just a
>>> passive, temporary solution to pathogens in the immediate environment
>>> only,
>>> not something that ³guides² the immune system. -CS
>>> * ³Immune networks² means something like the following: An
> anti-antibody
>>> is
>>> made that has same 3D shape as antigen, then an anti-anti-antibody is
>>> made
>>> that again can react against the original antigen. This is so-called
>>> idiotypic network theory. Not something I¹m really eager to get into.
>>> Cool
>>> idea though. The problem is to get an immune response you need all that
>>> ³damage² signal and probably that spells trouble for the idiotypic
>>> network,
>>> although never write something off completely in science, especially
>>> immunology, it might appear later.
>>> To unsubscribe, send a message to with
>>> "unsubscribe asa" (no quotes) as the body of the message.
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Received on Sun Dec 6 11:10:55 2009

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