期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 51, 页码 20503-20508出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1316179110
关键词
PIP2; calcium; vesicle fusion
资金
- Ministerio de Economia y Competitividad (MINECO), Spain-Fondo Europeo de Desarrollo Regional (FEDER) [BIO2011-24333]
- MINECO, Spain-FEDER [BFU2011-22828]
- Fundacion Seneca, Region de Murcia [08700/PI/08]
- Junta para la Amplificacion de Estudios postdoctoral contract from Consejo Superior de Investigaciones Cientificas-Fondo Social Europeo
- MINECO
Proteins containing C2 domains are the sensors for Ca2+ and PI(4,5)P-2 in a myriad of secretory pathways. Here, the use of a free-mounting system has enabled us to capture an intermediate state of Ca2+ binding to the C2A domain of rabphilin 3A that suggests a different mechanism of ion interaction. We have also determined the structure of this domain in complex with PI(4,5)P-2 and IP3 at resolutions of 1.75 and 1.9 angstrom, respectively, unveiling that the polybasic cluster formed by strands beta 3-beta 4 is involved in the interaction with the phosphoinositides. A comparative study demonstrates that the C2A domain is highly specific for PI(4,5)P-2/PI(3,4,5)P-3, whereas the C2B domain cannot discriminate among any of the diphosphorylated forms. Structural comparisons between C2A domains of rabphilin 3A and synaptotagmin 1 indicated the presence of a key glutamic residue in the polybasic cluster of synaptotagmin 1 that abolishes the interaction with PI(4,5)P-2. Together, these results provide a structural explanation for the ability of different C2 domains to pull plasma and vesicle membranes close together in a Ca2+-dependent manner and reveal how this family of proteins can use subtle structural changes to modulate their sensitivity and specificity to various cellular signals.
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