Distinct ligand-dependent and independent modes of thyroid hormone receptor (TR)/PGC-1α interaction

► Thyroid Hormone Receptor (TR) binds the coactivator PGC-1α in two ways. ► TR AF-2 makes T3-dependent contacts between AF-2 and the PGC-1α LxxLL. ► TR AF-1 binds the PGC-1α N-terminus. ► TR AF-1 is needed for use of PGC-1α C-terminal activation domains. ► We propose TR AF-1 triggers sequential use of PGC-1α activation functions.