Site-specific phosphorylation affects the structure and interactions of the Ycf1p R region

August 24, 2026| Source: PNAS

Many ATP-binding cassette (ABC) proteins function in active transport of solutes across biological membranes. At minimum, ABC proteins contain two repeats of a transmembrane domain (TMD) and a nucleotide binding domain (NBD). In many ABC proteins, the TMD-NBD halves are connected by an intrinsically disordered linker that regulates the activity of the ABC protein through phosphorylation. These regulatory (R) regions are often invisible or at low-resolution in cryo-EM maps. Thus, information about how R region phosphorylation controls ABC transporter activity is missing. Using NMR spectroscopy, we discern the structural features and interactions of the R region from the yeast cadmium factor 1 protein (Ycf1p), a C subfamily ABC protein that is homologous to human multidrug resistance protein 1. Our data show that the entire R region possesses residual secondary structure that changes with phosphorylation, including for often-invisible R region segments. The data demonstrate R region interactions with NBD1 and also with NBD2. NBD/R region interactions depend on the phosphorylation state of the R region and on the nucleotide-bound and oligomeric states of the NBDs, indicating how R region interactions change during the transport cycle. Complementary biochemical studies show that R region phosphorylation affects the ATPase activity of the NBDs. Yeast viability assays highlight the importance of R region residual structure and interactions on Ycf1p activity. The structural, biochemical, and in vivo studies enhance our molecular-level understanding of how R region affects the transport cycle of Ycf1p and related ABC proteins.

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