. Functional analysis of the transmembrane domains of presenilin 1: participation of transmembrane domains 2 and 6 in the formation of initial substrate-binding site of gamma-secretase. J Biol Chem. 2010 Jun 25;285(26):19738-46. PubMed.

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  1. This report provides a very thorough and systematic analysis of the role of the various transmembrane domains of PS1 in γ-secretase assembly, stability and activation. The evidence largely supports the role of specific TM domains in the various steps in the maturation of the protease complex as laid out schematically in Figure 9. This includes the role of TM2 and the luminal region of TM6 in the formation of the initial substrate binding site: swapping these regions with those of another unrelated membrane protein leads to the inability of a photoaffinity helical peptide probe targeted to this initial substrate binding site from labeling PS1. These two TM regions are apparently critical to the formation of this binding site, but whether they are both direct contributors to the binding site is not clear. It could be, for instance, that TM2 is not part of the initial substrate binding site but can nevertheless affect the conformation of this binding site. Some chemical crosslinking evidence is provided that TM2 is near TM9, the latter previously being implicated in binding and lateral gating of substrate. However, the evidence for TM2 proximity to TM9 is rather weak, and such proximity would not mean that TM2 is necessarily part of the substrate binding site.

  2. These authors take one of the helices of presenilin at a time, replace it
    with a helix of an unrelated protein and then measure its function. If the
    helix they exchange is important for a certain function, then the modified
    presenilin should no longer be able to show this function. It is like
    exchanging the individual parts of a car with, say, parts of household
    appliances. If you exchange the motor of the car with a vacuum cleaner and
    then try to start the car and it won't, then you have found out that the
    motor is necessary to drive the car. However if you push this car it will
    still move, so the motor is obviously important for driving but not in
    general for the ability of the car to be moved.

    In essence, Watanabe et al do the same thing with presenilin and its
    helices. The n-terminal domain has 6 helices (the C-terminal domain, of
    which we have determined the structure has 3). By exchanging every domain
    individually, the authors found that helix2 and helix6 are involved in
    binding of helical peptides such as βamyloid precursor protein. They
    also found that helix9, which is part of our structure, is involved in
    substrate binding. Understanding where the substrate binds is very
    important. As a field, we need lots of information about which sites bind
    specific substrates and which are involved in processing of APP. Only with
    such very detailed information will we able to develop drugs that inhibit
    formation of the Aβ peptide but not other functions presenilin is
    involved in.

    In this sense both this and our paper provide complementary information
    and provide another small but important piece of the puzzle.

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