{Reference Type}: Journal Article
{Title}: The structure of an Hsp90-immunophilin complex reveals cochaperone recognition of the client maturation state.
{Author}: Lee K;Thwin AC;Nadel CM;Tse E;Gates SN;Gestwicki JE;Southworth DR;
{Journal}: Mol Cell
{Volume}: 81
{Issue}: 17
{Year}: 09 2021 2
{Factor}: 19.328
{DOI}: 10.1016/j.molcel.2021.07.023
{Abstract}: The Hsp90 chaperone promotes folding and activation of hundreds of client proteins in the cell through an ATP-dependent conformational cycle guided by distinct cochaperone regulators. The FKBP51 immunophilin binds Hsp90 with its tetratricopeptide repeat (TPR) domain and catalyzes peptidyl-prolyl isomerase (PPIase) activity during folding of kinases, nuclear receptors, and tau. Here we determined the cryoelectron microscopy (cryo-EM) structure of the human Hsp90:FKBP51:p23 complex to 3.3 Å, which, together with mutagenesis and crosslinking analyses, reveals the basis for cochaperone binding to Hsp90 during client maturation. A helix extension in the TPR functions as a key recognition element, interacting across the Hsp90 C-terminal dimer interface presented in the closed, ATP conformation. The PPIase domain is positioned along the middle domain, adjacent to Hsp90 client binding sites, whereas a single p23 makes stabilizing interactions with the N-terminal dimer. With this architecture, FKBP51 is positioned to act on specific client residues presented during Hsp90-catalyzed remodeling.