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C2 Domains of Protein Kinase C Isoforms α, β, and γ:  Activation Parameters and Calcium Stoichiometries of the Membrane-Bound State

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Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309-0215, and Departamento de Bioquimica y Biologia Molecular (A), Facultad de Veterinaria, Universidad de Murcia, Apartado de Correos 4021, E30080 Murcia, Spain
Cite this: Biochemistry 2002, 41, 38, 11411–11424
Publication Date (Web):August 28, 2002
https://doi.org/10.1021/bi026041k
Copyright © 2002 American Chemical Society

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    Abstract

    The independently folding C2 domain motif serves as a Ca2+-dependent membrane docking trigger in a large number of Ca2+ signaling pathways. A comparison was initiated between three closely related C2 domains from the conventional protein kinase C subfamily (cPKC, isoforms α, β, and γ). The results reveal that these C2 domain isoforms exhibit some similarities but are specialized in important ways, including different Ca2+ stoichiometries. In the absence of membranes, Ca2+ affinities of the isolated C2 domains are similar (2-fold difference) while Hill coefficients reveal cooperative Ca2+ binding for the PKCβ C2 domain but not for the PKCα or PKCγ C2 domain (H = 2.3 ± 0.1 for PKCβ, 0.9 ± 0.1 for PKCα, and 0.9 ± 0.1 for PKCγ). When phosphatidylserine-containing membranes are present, Ca2+ affinities range from the sub-micromolar to the micromolar (7-fold difference) ([Ca2+]1/2 = 0.7 ± 0.1 μM for PKCγ, 1.4 ± 0.1 μM for PKCα, and 5.0 ± 0.2 μM for PKCβ), and cooperative Ca2+ binding is observed for all three C2 domains (Hill coefficients equal 1.8 ± 0.1 for PKCβ, 1.3 ± 0.1 for PKCα, and 1.4 ± 0.1 for PKCγ). The large effects of membranes are consistent with a coupled Ca2+ and membrane binding equilibrium, and with a direct role of the phospholipid in stabilizing bound Ca2+. The net negative charge of the phospholipid is more important to membrane affinity than its headgroup structure, although a slight preference for phosphatidylserine is observed over other anionic phospholipids. The Ca2+ stoichiometries of the membrane-bound C2 domains are detectably different. PKCβ and PKCγ each bind three Ca2+ ions in the membrane-associated state; membrane-bound PKCα binds two Ca2+ ions, and a third binds weakly or not at all under physiological conditions. Overall, the results indicate that conventional PKC C2 domains first bind a subset of the final Ca2+ ions in solution, and then associate weakly with the membrane and bind additional Ca2+ ions to yield a stronger membrane interaction in the fully assembled tertiary complex. The full complement of Ca2+ ions is needed for tight binding to the membrane. Thus, even though the three C2 domains are 64% identical, differences in Ca2+ affinity, stoichiometry, and cooperativity are observed, demonstrating that these closely related C2 domains are specialized for their individual functions and contexts.

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     Support provided by NIH Grants GM R01-63235 (to J.J.F.) and GM T32-07135 (to S.C.K.) and by DGESIC Grant PB98-0389 (to J.C.G.-F.).

     University of Colorado.

    §

     Universidad de Murcia.

    *

     To whom correspondence should be addressed. E-mail:  falke@ colorado.edu. Telephone:  (303) 492-3503. Fax:  (303) 492-5894.

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