Mechanism of Gαi-mediated Inhibition of Type V Adenylyl Cyclase*

  1. Jun Chen
  1. From the Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, Texas 77030


The topology of mammalian adenylyl cyclase reveals an integral membrane protein composed of an alternating series of membrane and cytoplasmic domains (C1 and C2). The stimulatory G protein, Gαs, binds within a cleft in the C2 domain of adenylyl cyclase while Gαi binds within the opposite cleft in the C1domain. The mechanism of these two regulators also appears to be in opposition. Activation of adenylyl cyclase by Gαs or forskolin results in a 100-fold increase in the apparent affinity of the two domains for one another. We show herein that Gαireduces C1/C2 domain interaction and thus formation of the adenylyl cyclase catalytic site. Mutants that increase the affinity of C1 for C2 decrease the ability of Gαi to inhibit the enzyme. In addition, Gαi can influence binding of molecules to the catalytic site, which resides at the C1/C2 interface. Adenylyl cyclase can bind substrate analogs in the presence of Gαi but cannot simultaneously bind Gαi and transition state analogs such as 2′d3′-AMP. Gαi also cannot inhibit the membrane-bound enzyme in the presence of manganese, which increases the affinity of adenylyl cyclase for ATP and substrate analogs. Thus homologous G protein α-subunits promote bidirectional regulation at the domain interface of the pseudosymmetrical adenylyl cyclase enzyme.

  • Abbreviations:
    adenylyl cyclase(s)
    α-subunit of the inhibitory G protein of adenylyl cyclase
    α-subunit of the G protein that stimulates adenylyl cyclase
    guanosine 5′-O-(2-thio)triphosphate
    α,β-methylene adenosine 5′-triphosphate
    2′-deoxyadenosine 3′-monophosphate
    2′,5′-dideoxyadenosine 3′-triphosphate
    • Received April 23, 2002.
    • Revision received June 4, 2002.
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    This Article

    1. The Journal of Biological Chemistry 277, 28823-28829.
    1. All Versions of this Article:
      1. M203962200v1
      2. 277/32/28823 (most recent)

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