Coupled intra- and interdomain dynamics support domain cross-talk in Pin1

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Biology

Background:

• Multidomain proteins utilize interdomain interactions for function.
• Human Pin1, a mitotic regulator, comprises a Trp-Trp (WW) domain and a peptidyl-prolyl isomerase (PPIase) domain.
• The precise mechanism by which substrate binding to the WW domain affects interdomain cross-talk in Pin1 is not fully understood.

Purpose of the Study:

• To investigate the interdomain interactions of human Pin1.
• To elucidate how substrate binding influences these interactions.
• To explore the dynamic modular architecture of Pin1 and its implications for other cell-cycle proteins.

Main Methods:

• Nuclear Magnetic Resonance (NMR) paramagnetic relaxation enhancement (PRE) spectroscopy.
• All-atom molecular dynamics (MD) simulations (4.5-μs).

Main Results:

• Apo-Pin1 samples a broader range of interdomain contacts than previously structurally characterized.
• Substrate binding to the WW domain induces simultaneous changes in interdomain separation and WW domain conformation.
• MD simulations revealed correlations between interdomain distance fluctuations and WW domain interresidue contacts crucial for substrate binding.

Conclusions:

• Pin1 exhibits a dynamic modular architecture where intra- and interdomain conformational fluctuations are coupled.
• The sampled conformations in apo-Pin1 are pre-organized for substrate binding.
• The WW-PPIase domain cross-talk mechanism in Pin1 may be a general principle for other cell-cycle proteins.