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The C2A-C2B linker defines the high affinity Ca(2+) binding mode of rabphilin-3A.

Authors: Montaville, P  Schlicker, C  Leonov, A  Zweckstetter, M  Sheldrick, GM  Becker, S 
Citation: Montaville P, etal., J Biol Chem. 2007 Feb 16;282(7):5015-25. Epub 2006 Dec 13.
Pubmed: (View Article at PubMed) PMID:17166855
DOI: Full-text: DOI:10.1074/jbc.M606746200

The Ca(2+) binding properties of C2 domains are essential for the function of their host proteins. We present here the first crystal structures showing an unexpected Ca(2+) binding mode of the C2B domain of rabphilin-3A in atomic detail. Acidic residues from the linker region between the C2A and C2B domains of rabphilin-3A interact with the Ca(2+)-binding region of the C2B domain. Because of these interactions, the coordination sphere of the two bound Ca(2+) ions is almost complete. Mutation of these acidic residues to alanine resulted in a 10-fold decrease in the intrinsic Ca(2+) binding affinity of the C2B domain. Using NMR spectroscopy, we show that this interaction occurred only in the Ca(2+)-bound state of the C2B domain. In addition, this Ca(2+) binding mode was maintained in the C2 domain tandem fragment. In NMR-based liposome binding assays, the linker was not released upon phospholipid binding. Therefore, this unprecedented Ca(2+) binding mode not only shows how a C2 domain increases its intrinsic Ca(2+) affinity, but also provides the structural base for an atypical protein-Ca(2+)-phospholipid binding mode of rabphilin-3A.


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RGD Object Information
RGD ID: 8554421
Created: 2014-05-08
Species: All species
Last Modified: 2014-05-08
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.