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Vol. 9, Issue 8, 1981-1994, August 1998
Laboratorium für Molekulare Biologie, Genzentrum der
Universität München, D-81377 München, Germany
Recruitment of intracellular proteins to the plasma membrane
is a commonly found requirement for the initiation of signal transduction events. The recently discovered pleckstrin homology (PH)
domain, a structurally conserved element found in ~100 signaling proteins, has been implicated in this function, because some PH domains
have been described to be involved in plasma membrane association.
Furthermore, several PH domains bind to the phosphoinositides phosphatidylinositol-(4,5)-bisphosphate and
phosphatidylinositol-(3,4,5)-trisphosphate in vitro, however,
mostly with low affinity. It is unclear how such weak interactions can
be responsible for observed membrane binding in vivo as well as the
resulting biological phenomena. Here, we investigate the structural and
functional requirements for membrane association of cytohesin-1, a
recently discovered regulatory protein of T cell adhesion. We
demonstrate that both the PH domain and the adjacent carboxyl-terminal
polybasic sequence of cytohesin-1 (c domain) are necessary for plasma
membrane association and biological function, namely interference with
Jurkat cell adhesion to intercellular adhesion molecule 1. Biosensor
measurements revealed that
phosphatidylinositol-(3,4,5)-trisphosphate binds to the PH
domain and c domain together with high affinity (100 nM), whereas the
isolated PH domain has a substantially lower affinity (2-3 µM). The
cooperativity of both elements appears specific, because a chimeric
protein, consisting of the c domain of cytohesin-1 and the PH domain of
the 
-adrenergic receptor kinase does not associate with membranes,
nor does it inhibit adhesion. Moreover, replacement of the c domain of
cytohesin-1 with a palmitoylation-isoprenylation motif partially
restored the biological function, but the specific targeting to the
plasma membrane was not retained. Thus we conclude that two elements of
cytohesin-1, the PH domain and the c domain, are required and sufficient for membrane association. This appears to be a common mechanism for plasma membrane targeting of PH domains, because we
observed a similar functional cooperativity of the PH domain of
Bruton's tyrosine kinase with the adjacent Bruton's tyrosine kinase
motif, a novel zinc-containing fold.
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