2lm5
From Proteopedia
Solution structure of Ca2+-CIB1 in complex with the cytoplasmic domain of the integrin aIIb subunit
Structural highlights
FunctionCIB1_HUMAN May convert the inactive conformation of integrin alpha-IIb/beta3 to an active form through binding to the integrin cytoplasmic domain. Induces cell migration and spreading mediated through integrin (possibly via focal adhesion complexes). Functions as a negative regulator of stress activated MAP kinase (MAPK) signaling pathways. May play a role in regulation of apoptosis. Interacts with and up-regulates PTK2/FAK1 activity. Down regulates inositol 1,4,5-trisphosphate receptor-dependent calcium signaling. Participates in endomitotic cell cycle, a form of mitosis in which both karyokinesis and cytokinesis are interrupted and is a hallmark of megakaryocyte differentiation.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedCalcium and integrin binding protein 1 (CIB1) is a specific binding partner for the cytoplasmic domain of the alphaIIb subunit of the highly abundant platelet integrin alphaIIbbeta3. This protein has been suggested to be involved in the regulation of the activation of alphaIIbbeta3, a process leading to platelet aggregation and blood coagulation. In this work, the solution structure of the deuterated Ca(2+)-CIB1 protein complexed with an alphaIIb peptide was first determined through modern RDC-based NMR methods. Next, we generated a complex structure for CIB1 and the alphaIIb domain (Ca(2+)-CIB1/alphaIIb) using the program Haddock, which is based on experimental restraints obtained for the protein-peptide interface from cross-saturation NMR experiments. In this data-driven complex structure, the N-terminal alpha-helix of the cytoplasmic domain of alphaIIb is buried in the hydrophobic pocket of the C-lobe of Ca(2+)-CIB1. The C-terminal acidic tail of alphaIIb remains unstructured and likely interacts with several positively charged residues in the N-lobe of Ca(2+)-CIB1. A potential molecular mechanism for the CIB1-mediated activation of the platelet integrin could be proposed on the basis of the model structure of this protein complex. Another feature of this work is that, in the NMR cross-saturation experiments, we applied the selective radio frequency irradiation to the smaller binding partner (the alphaIIb peptide), and successfully detected the binding interface on the larger binding partner Ca(2+)-CIB1 through its selectively protonated methyl groups. This 'reverse' methodology has a broad potential to be employed to many other complexes where synthetic peptides and a suitably isotope-labeled medium- to large-sized protein are used to study protein-protein interactions. Structural basis for the activation of platelet integrin alphaIIbbeta3 by calcium- and integrin-binding protein 1.,Huang H, Vogel HJ J Am Chem Soc. 2012 Feb 29;134(8):3864-72. doi: 10.1021/ja2111306. Epub 2012 Feb , 16. PMID:22283712[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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