Structural Analysis of the Roles of CCT and PhLP1 in G Protein β Subunit Folding and Gβγ Dimer Assembly.

Defects in G protein signaling are implicated in host of disorders and diseases, which makes them high value therapeutic targets. While the function of the different G protein subunits has been well-characterized, little is known about their folding and assembly into complexes. The previous work from our lab showed that CCT and its co-chaperone PhLP1 are required for the folding of the Gβ subunits and their assembly into complexes with Gγ subunits into the Gβγ dimer. To understand the molecular mechanism of Gβ folding by CCT and PhLP1, we have captured the PhLP1-Gβ1-CCT complex and determined its structure by high resolution cryo-electron microscopy. The structure shows Gβ1 in an unexpected position, sitting between the two CCT rings and interacting with the N- and C- termini of several CCT subunits. In this position, Gβ appears to have reached a near-native β-propeller fold. This result confirms the importance of the terminal regions of the CCT subunits in binding β-propeller proteins, as we recently observed with Gβ-like mLST8 subunit of the mTOR complex (Cuellar et al. 2019 Nature Commun. 10, 2865). The structure also elucidates the role of PhLP1 in Gβ1 folding. The PhLP1 C-terminal domain binds to the apical domains of the CCT3 and CCT6 subunits, while its N-terminal domain extends down to interact with Gβ1 between the CCT rings. The structure explains why the PhLP1 N-terminal domain is essential in triggering the release of Gβ1 from CCT to interact with Gγ. These findings suggest that a mimetic of the interaction between the N-terminal domain of PhLP1 and Gβ1 could block Gβγ assembly and interfere with G protein signaling in disease states caused by excessive G protein signaling. © FASEB.

Citation

Yujin Kwon. Structural Analysis of the Roles of CCT and PhLP1 in G Protein β Subunit Folding and Gβγ Dimer Assembly. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2022 May;36 Suppl 1

PMID: 35554638

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