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Journal of Undergraduate Research

Keywords

PhLP1-Gβ-CCT complex, G protein heterotrimer, Gβγ dimers

College

Physical and Mathematical Sciences

Department

Chemistry and Biochemistry

Abstract

Cells detect and respond to a myriad of extracellular signals via seven-transmembrane G protein-coupled receptors and their associated G protein signaling pathways. The pathway is initiated by the binding of a signaling molecule, such as a hormone or neurotransmitter, to its binding site on the extracellular side of the receptor. This interaction activates the G protein heterotrimer, composed of Gβ, Gβ, and Gβ subunits, which functions by propagating the signal throughout the cell. First, however, the G protein heterotrimer must be assembled from its nascent polypeptides. The initial step in this process is the formation of the Gβγ dimer. Gβγ is an obligate dimer in which neither subunit is able to fold into a stable structure on its own. A fundamental question that has persisted for years is how the Gβγ dimer can form when the individual subunits are unstable. Recently, however, strong biochemical evidence from our lab and others showed that the Gβγ-binding protein, phosducin-like protein 1 (PhLP1) acts as a co-chaperone with the cytosolic chaperonin CCT to fold Gβ and promote its interaction with Gγ (1). Since then, we have spent considerable time and effort to uncover the molecular mechanism by which PhLP1 and CCT work together to assemble Gβγ dimers. We had determined the structures of two intermediates in the Gβγ assembly process, the Gβ-CCT complex and the PhLP1-Gβ-CCT complex, by cryo-electron microscopy to 13 Å resolution (3), but even with this major achievement the exact binding site of Gβ remained a mystery.

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