Structural and Functional Implication of Natural Variants of Gαs.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

GTP-Binding Protein alpha Subunits, Gs*/chemistry ; GTP-Binding Protein alpha Subunits, Gs*/genetics ; GTP-Binding Protein alpha Subunits, Gs*/metabolism; Guanosine Diphosphate/metabolism ; Guanosine Triphosphate/metabolism ; Parathyroid Hormone/metabolism ; Signal Transduction ; Humans ; Pseudohypoparathyroidism/genetics ; Protein Conformation

Heterotrimeric guanine nucleotide-binding proteins (G proteins) are among the most important cellular signaling components, especially G protein-coupled receptors (GPCRs). G proteins comprise three subunits, Gα, Gβ, and Gγ. Gα is the key subunit, and its structural state regulates the active status of G proteins. Interaction of guanosine diphosphate (GDP) or guanosine triphosphate (GTP) with Gα switches G protein into basal or active states, respectively. Genetic alteration in Gα could be responsible for the development of various diseases due to its critical role in cell signaling. Specifically, loss-of-function mutations of Gαs are associated with parathyroid hormone-resistant syndrome such as inactivating parathyroid hormone/parathyroid hormone-related peptide (PTH/PTHrP) signaling disorders (iPPSDs), whereas gain-of-function mutations of Gαs are associated with McCune-Albright syndrome and tumor development. In the present study, we analyzed the structural and functional implications of natural variants of the Gαs subtype observed in iPPSDs. Although a few tested natural variants did not alter the structure and function of Gαs, others induced drastic conformational changes in Gαs, resulting in improper folding and aggregation of the proteins. Other natural variants induced only mild conformational changes but altered the GDP/GTP exchange kinetics. Therefore, the results shed light on the relationship between natural variants of Gα and iPPSDs.

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Keywords: G protein; GDP/GTP; GNAS; conformation; inactivating PTH/PTHrP signaling disorders; natural variants

146-91-8 (Guanosine Diphosphate)
86-01-1 (Guanosine Triphosphate)
0 (Parathyroid Hormone)
EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gs)

Date Created: 20230225 Date Completed: 20230328 Latest Revision: 20230328

20240628

PMC9959179

10.3390/ijms24044064

36835474