Fig. 2

Topological illustration of HCAR1, HCAR2 and HCAR3 highlighting missense variants identified in the AHCC, TCGA, and previous functional studies. A HCAR1 (Q9BXC0); red: HCAR1 p.P20A detected in a BC case from the AHCC; orange: HCAR1 missense variants detected in TCGA BC cases, including p.Y74C, p.D112N, p.S172L, p.H257R; light blue/silver: p.L241F detected in both TCGA and AHCC BC cases; yellow: HCAR1 transmembrane domain variants, p.R99A, p.Y233A, p.R240A, and p.T267A, reported by Liu et al. to diminish the response to L-lactate [33]; green: HCAR1 residue R71 and motif C165-E166-S167-F168 identified by Kuei et al. as being critical for protein function [31]; blue: HCAR1 extracellular Cys residues, C6, 7, 88, 157, 165 (green) and 252, reported by Kuei et al. to abolish receptor activity when substituted with alanine or serine [31]; purple: HCAR1 variants p.A110V, p.S172L (covered by orange since it overlaps with variant detected in TCGA), and p.D253H identified by Doyle et al. as loss-of-function variants [32]. B HCAR2 (Q8TDS4); orange: HCAR2 missense variants detected in TCGA BC cases, including TCGA variants p.L11P, p.R142W, p.M167L, p.P168L, p.G173T, p.R311H, p.M346V, and p.G350S; yellow: N86/W91, R111, S178, F276, and Y284 were reported by Tunaru et al. as critical for binding of nicotinic acid [29]; green: Yasuda et al. identified an atypical motif N17-C18-C19 that is crucial for surface trafficking. They also identified C100, C177, C183, and C266, in the extracellular regions, which are important for HCAR2 activation [30]; blue: Li et al. identified a sequence of residues from 329–343 that plays a crucial role in keeping HCAR2 in an inactive conformation [28]. C HCAR3 (P49019); red: HCAR3 p.R187Q identified in a BC case in the AHCC; orange: HCAR3 missense variants detected in TCGA BC cases, including p.R3W, p.A27V, and p.R216W