Molecular Modeling of Structures and Interaction of Human Corticotropin-Releasing Factor (CRF) Binding Protein and CRF Type-2 Receptor.
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ABSTRACT: The corticotropin-releasing factor (CRF) system is a key mediator of the stress response and addictive behavior. The CRF system includes four peptides: The CRF system includes four peptides: CRF, urocortins I-III, CRF binding protein (CRF-BP) that binds CRF with high affinity, and two class B G-protein coupled receptors CRF1R and CRF2R. CRF-BP is a secreted protein without significant sequence homology to CRF receptors or to any other known class of protein. Recently, it has been described a potentiation role of CRF-BP over CRF signaling through CRF2R in addictive-related neuronal plasticity and behavior. In addition, it has been described that CRF-BP is capable to physically interact specifically with the ? isoform of CRF2R and acts like an escort protein increasing the amount of the receptor in the plasma membrane. At present, there are no available structures for CRF-BP or for full-length CRFR. Knowing and studying the structure of these proteins could be beneficial in order to characterize the CRF-BP/CRF2?R interaction. In this work, we report the modeling of CRF-BP and of full-length CRF2?R and CRF2?R based on the recently solved crystal structures of the transmembrane domains of the human glucagon receptor and human CRF1R, in addition with the resolved N-terminal extracellular domain of CRFRs. These models were further studied using molecular dynamics simulations and protein-protein docking. The results predicted a higher possibility of interaction of CRF-BP with CRF2?R than CRF2?R and yielded the possible residues conforming the interacting interface. Thus, the present study provides a framework for further investigation of the CRF-BP/CRF2?R interaction.
SUBMITTER: Slater PG
PROVIDER: S-EPMC5826306 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
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