Structural and Biochemical Characterization of CIB1

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CIB1 (CIB) is an EF-hand containing protein that binds the platelet αIIbβ3 integrin and several serine/threonine kinases to modulate their functions. The crystal structure for Ca2+-bound CIB1 has been determined at 2.0 Å resolution and reveals a compact α-helical protein containing four EF-hands, the last two of which bind calcium ions. CIB1 shares high structural similarity with calcineurin B (CnB) and the neuronal calcium sensor (NCS) family of EF-hand containing proteins. Most importantly, like CnB and NCS proteins, which possess a large hydrophobic pocket necessary for ligand binding, CIB1 contains a hydrophobic pocket that has been implicated in ligand binding by previous mutational analysis and NMR data. However, unlike several NCS proteins, Ca2+-bound CIB1 is largely monomeric whether bound to a relevant peptide ligand or ligand-free. Differences in structure, oligomeric state, and phylogeny define a new family of CIB1-related proteins that extends from arthropods to humans. In addition to binding αIIbβ3, CIB1 binds additional α integrins, including α2, α4, α5, αL, and αM with micromolar affinities. CIB1 inhibits agonist-induced activation of αIIbβ3, and future work will determine if CIB1 affects the activation states of these additional binding partners.

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