Investigating dynamic interdomain allostery in Pin1

Signaling proteins often sequester complementary functional sites in separate domains. How do the different domains communicate with one another? An attractive system to address this question is the mitotic regulator, human Pin1 (Lu et al., Nature 380:544–547, 1996). Pin-1 consists of two mutually tethered domains: a WW domain for substrate binding and a catalytic domain for peptidyl-prolyl isomerase (PPIase) activity. Pin1 accelerates the cis–trans isomerization of phospho-Ser/Thr-Pro (pS/T-P) motifs within proteins regulating the cell cycle and neuronal development. The early X-ray (Ranganathan et al., Cell 89:875–886, 1997; Verdecia et al., Nat Struct Biol 7:639–643, 2000) and solution NMR studies (Bayer et al., J Biol Chem 278:26183–26193, 2003; Jacobs et al., J Biol Chem 278:26174–26182, 2003) of Pin1 indicated inter- and intradomain motions. We have explored how such motions might affect interdomain communication, using NMR. Our accumulated results indicate substrate binding to Pin1 WW domain changes the intra/interdomain mobility, thereby altering substrate activity in the distal PPIase domain catalytic site. Thus, Pin1 shows evidence of dynamic allostery, in the sense of Cooper and Dryden (Eur J Biochem 11:103–109, 1984). We highlight our results supporting this conclusion and summarize them via a simple speculative model of conformational selection.