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Originally published In Press as doi:10.1074/jbc.M106573200 on October 11, 2001

J. Biol. Chem., Vol. 276, Issue 50, 47715-47724, December 14, 2001
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The Conserved Sites for the FK506-binding Proteins in Ryanodine Receptors and Inositol 1,4,5-Trisphosphate Receptors Are Structurally and Functionally Different*

Geert BultynckDagger §, Daniela Rossi, Geert CallewaertDagger , Ludwig MissiaenDagger , Vincenzo Sorrentino||, Jan B. ParysDagger , and Humbert De SmedtDagger **

From the Dagger  Laboratorium voor Fysiologie, K.U.Leuven Campus Gasthuisberg O/N, Herestraat 49, B-3000 Leuven, Belgium, the  Section of Molecular Medicine, Department of Neuroscience, University of Siena, Siena I-531000, Italy, and || DIBIT, San Raffaele Scientific Institute, I-20132 Milan, Italy

We compared the interaction of the FK506-binding protein (FKBP) with the type 3 ryanodine receptor (RyR3) and with the type 1 and type 3 inositol 1,4,5-trisphosphate receptor (IP3R1 and IP3R3), using a quantitative GST-FKBP12 and GST-FKBP12.6 affinity assay. We first characterized and mapped the interaction of the FKBPs with the RyR3. GST-FKBP12 as well as GST-FKBP12.6 were able to bind ~30% of the solubilized RyR3. The interaction was completely abolished by FK506, strengthened by the addition of Mg2+, and weakened in the absence of Ca2+ but was not affected by the addition of cyclic ADP-ribose. By using proteolytic mapping and site-directed mutagenesis, we pinpointed Val2322, located in the central modulatory domain of the RyR3, as a critical residue for the interaction of RyR3 with FKBPs. Substitution of Val2322 for leucine (as in IP3R1) or isoleucine (as in RyR2) decreased the binding efficiency and shifted the selectivity to FKBP12.6; substitution of Val2322 for aspartate completely abolished the FKBP interaction. Importantly, the occurrence of the valylprolyl residue as alpha -helix breaker was an important determinant of FKBP binding. This secondary structure is conserved among the different RyR isoforms but not in the IP3R isoforms. A chimeric RyR3/IP3R1, containing the core of the FKBP12-binding site of IP3R1 in the RyR3 context, retained this secondary structure and was able to interact with FKBPs. In contrast, IP3Rs did not interact with the FKBP isoforms. This indicates that the primary sequence in combination with the local structural environment plays an important role in targeting the FKBPs to the intracellular Ca2+-release channels. Structural differences in the FKBP-binding site of RyRs and IP3Rs may contribute to the occurrence of a stable interaction between RyR isoforms and FKBPs and to the absence of such interaction with IP3Rs.

* This work was supported in part by Grant 3.0207.99 from the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (to H. D. S. and J. B. P.), by Grant P4/23 from the Program on Interuniversity Poles of Attraction (to J. B. P., G. C., H. D. S., and L. M.), by Grant 99/08 from the Concerted Actions of the K. U. Leuven (to L. M., H. D. S., G. C., and J. B. P.), and by grants from Telethon and Murst (to V. S.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Recipient of a predoctoral fellowship from the Vlaams Instituut voor de Bevordering van het Wetenschappelijk-Technologisch Onderzoek in de Industrie.

** To whom correspondence should be addressed: Laboratory for Physiology, K. U. Leuven, Campus Gasthuisberg O/N, Herestraat 49, B-3000 Leuven, Belgium. Tel.: 32-16-345725; Fax: 32-16-345991; E-mail: humbert.desmedt@med.kuleuven.ac.be.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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