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. 2003 Jan 6;160(1):89–99. doi: 10.1083/jcb.200210115

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Copyright © 2003, The Rockefeller University Press

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Figure 9. — Hypothetical model for receptor- induced membrane recruitment and activation of heterodimeric PI3Kγ. fMLP receptor, a prototypical heptahelical receptor coupled to G_i proteins. PI3Kγ; the cytosolic enzyme consists of a noncatalytic p101 subunit, which is in a tight complex with p110γ, thereby stabilizing p101. The NH₂ and COOH termini of p101 and p110γ are oriented in close proximity, respectively. Contact sites involve the NH₂ termini of both subunits. The modular domain structure of p110γ (RBD, Ras binding domain; C2, C2 domain; hel, helical domain; N-cat, C-cat, NH₂- and COOH-terminal lobes of the catalytic domain) is based on the crystal structure of an NH₂-terminally truncated p110γ. (A) Membrane recruitment. The agonist-stimulated receptor induces the release of Gβγ from G_i proteins (dotted arrow). Gβγ recruits the PI3Kγ heterodimer to the plasma membrane (dotted arrow) by binding to the noncatalytic p101 (hollow arrow). Accordingly, Gβγ and p101 function as a membrane anchor and an adaptor for PI3Kγ, respectively. In addition, the C2 domain of p110γ may facilitate membrane attachment through interaction with phospholipids. p101 may also affect the interaction of PI3Kγ with the lipid interface. Membrane-attached PI3Kγ exhibits basal enzymatic activity. (B) Allosteric activation. At the membrane, Gβγ activates PI3Kγ by direct interaction with p110γ (hollow arrows). This stimulation does not require p101. However, p101 may participate in Gβγ-induced stimulation of membrane-attached p110γ. The stoichiometry of the Gβγ–PI3Kγ interaction is unknown, i.e., Gβγ may interact with p101 and p110γ through individual or common binding sites. Gβγ binds to the NH₂- and COOH-terminal part of p110γ, the latter harboring the catalytic domain. Thus, Gβγ may allosterically activate PI3Kγ through a conformational change in the catalytic domain. Accordingly, Gβγ significantly increases V_max of PtdIns-3,4,5-P₃ production. PtdIns-3,4,5-P₃, in turn, recruits PH domain–containing effectors such as GRP1 or Btk to the plasma membrane (dotted arrow).