The study is being published in Science Express, an advanced online edition of the journal Science, on April 5. It will appear in the print version of Science later this spring.
In findings the authors called "unexpected and striking," the study found that a new regulating messenger IP4, a small soluble molecule, augments the binding of three different PH domain proteins to one of the most commonly recognized membrane lipids, PIP3. The study also showed that inhibiting production of IP4 can result in reduced protein binding to membranes and reduced activation of key signaling molecules in developing T cells, leading to a block of T cell maturation and to severe immunodeficiency in animal models.
"This study changes how we think about the T cell receptor signaling process and a well established general signaling mechanism, protein recruitment to membranes through PH domains," said Karsten Sauer, a Scripps Research scientist who led the study. "For the first time, we have clearly established a new way through which the PH domain can be positively regulated in vivo-IP4 augments the binding of PIP3 to these domains. In fact, it resembles PIP3. Until our study, the widely accepted idea was that recruitment of PIP3 binding PH domains to the membrane was primarily regulated by the supply and turnover of PIP3. The second completely new finding is that PH domain proteins can form aggregates through their PH domains. PH domain aggregation may enhance the membrane binding process."
Sauer suggests models for how IP4 might augment the binding of PIP3. In one, IP4 binds to a PH domain, changing its structure to one with a high affinity for IP4 and PIP3, a process commonly known as the "induced fit" model. In the second model, the PH domain pre-exists as an aggregate; IP4 binding to one subunit forces changes in the other subunit(s) so that they bind PIP3 with greater ease. This process is commonly known as an allosteric or cooperative mechanis
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Contact: Keith McKeown
kmckeown@scripps.edu
858-784-8134
Scripps Research Institute
5-Apr-2007