Glycine betaine transporter, BetP. BetP is a transporter with three different functions: betaine transport, osmosensing, and osmoregulation (Krämer and Morbach 2004).  The x-ray structure is known (3PO3; 2WIT; Ressl et al., 2009). Regulatory crosstalk in the trimeric BetP has been reported (Gärtner et al., 2011). An extracellular K⁺ -dependent interaction site modulates betaine-binding (Ge et al., 2011). The porter is trimeric and exhibits structural asymmetry (Tsai et al., 2011). The C-terminal domain is involved in osmosensing and is trimeric like wild-type BetP.  The two Na⁺ binding sites are between TMSs 1 and 8 in the first and second 5 TMS repeats, and between the equivalent TMSs 6 and 3 in the second and first repeats, respectively (Khafizov et al. 2012). interdependent binding of betaine and two sodium ions is observed during the coupling process. All three sites undergo progressive reshaping and dehydration during the alternating-access cycle, with the most optimal coordination of all substrates found in the closed state (Perez et al. 2014). BetP is active and regulated only when negatively charged lipids such as phosphatidyl glycerol are present, and the mechanism has been discussed (Güler et al. 2016).  The K⁺-sensing C-terminal domain results in K⁺-dependent cooperative betaine-binding (Ge et al. 2011). BetP is a homotrimer lacking exact 3-fold symmetry. The observed differences may be due to crystal packing, or they may reflect different functional states of the transporter, related to osmosensing and osmoregulation (Ziegler et al. 2004). Intracellular K⁺ alters the conformation of the disordered C- and N-terminal domains to allosterically reconfigure TMSs 3, 8 and 10 to enhance betaine interactions. A map of the betaine binding site, at near single amino acid resolution, revealed a critical extrahelical H-bond mediated by TMS3 with betaine (Tantirimudalige et al. 2022). Hyperosmotic stress allosterically reconfigures the betaine binding pocket in BetP (Tantirimudalige et al. 2022). Both the N- and C-terminal (45 aas) segments participate in autoregulation, transducing changes in K⁺ concentrations as well as lipid bilayer properties to the integral membrane part of the protein. The C-terminal segment has short helical elements and an orientation that confines interactions (Leone et al. 2022).