Biology subjects

Taylor, H. D.

Publications and source records attributed to Taylor, H. D..

3 recordsLinked to original sources

bioRxiv2026

Positive cooperativity enhances coupling of a second G protein to a GPCR dimer

G protein-coupled receptors (GPCRs) are cell surface integral membrane proteins that transduce environmental, hormonal and neurotransmitter molecular signals into intracellular responses. Here we studied a class D1 fungal receptor, Ste2, an obligate dimer that couples two G proteins per dimer and show that coupling of the second G protein has an 18-fold higher affinity than coupling of the first. The molecular mechanism uncovered suggests that coupling of the first G protein to one protomer stabilizes the adjacent protomer in an active conformation with a pre-formed G protein coupling site, thus increasing the affinity for coupling of the second G protein. Protomer-based stabilization of an adjacent protomer in a unique conformational state within a dimer may represent a general mechanism by which oligomerization alters GPCR pharmacology.

biochemistry↗

bioRxiv2026

Disrupted RGS coupling underlies a clinically distinct subset of GNAO1-related disorder

Heterotrimeric G proteins are transducers for a wide variety of neurotransmitter receptors. Mutations in the G protein o subunit are implicated in an early-onset neurological condition, GNAO1-related disorder, that manifests as movement disorders, developmental delays, and/or epileptic seizures. In a screen of disease-linked mutations in Go, we identified a subset that had no obvious biochemical defects, warranting further investigation. By structural modeling, protein-protein binding experiments in vitro and in cells, as well as measures of downstream ion channel electrophysiology, we identified a subset that impairs interactions with regulator of G protein signaling (RGS) proteins. RGS proteins accelerate G protein GTPase activity and are therefore critical for proper neurotransmitter signaling. Further, synthesis of current clinical data revealed that patients harboring these variants have comparatively mild symptoms. Our study demonstrates the importance of RGS regulation in G protein function, cell signaling, and human neurobiology.

biochemistry↗

bioRxiv2026

Conserved Residues in the Gα interface show subtype specificity in Gβγ coupling

Although the structural basis of selective G-protein coupling to G protein coupled receptors (GPCRs) is well characterized, the mechanisms underlying selective interactions between distinct G subtypes (Gs, Gi, Gq, and G12/13) and G{beta}{gamma} remain poorly understood. While conserved residues in G subtypes are often assumed to have similar functions, they may instead modulate coupling selectivity by altering the frequency and stability of contacts at the G:G{beta}{gamma} interface. Using molecular dynamics (MD) simulations combined with the interpretable machine learning method, Bayesian Network Model (BNM), and protein-protein proximity (BRET) assays, we show that conserved residues in the two closely related Gi/o and Gq/11 subfamilies contribute differentially to G{beta}{gamma} coupling. These conserved residue "hotspots" on Gi and Gq produced divergent functional effects on G{beta}{gamma} coupling, indicating that conservation does not ensure functional equivalence. These findings suggest that local microenvironment and paralog-specific allosteric coupling shape how conserved interface residues contribute to protein-protein coupling. The framework provides a systematic approach for dissecting subtype-specific mechanisms, with implications for drug design and for annotating the functional relevance of disease-associated variants. The computational methods used here are broadly applicable to other homologous protein families.

molecular biology↗