Investigating Dynamic Interdomain Allostery in Pin1

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Signaling proteins utilize distinct domains for function, necessitating inter-domain communication mechanisms.
• Human Pin1, a mitotic regulator, possesses a WW domain for substrate binding and a peptidyl-prolyl isomerase (PPIase) catalytic domain.
• Pin1 regulates the cell cycle and neuronal development by isomerizing phospho-Ser/Thr-Pro motifs.

Purpose of the Study:

• To investigate how inter- and intradomain motions in Pin1 affect interdomain communication.
• To explore the functional consequences of substrate binding on Pin1's domain dynamics and catalytic activity.

Main Methods:

• Nuclear Magnetic Resonance (NMR) spectroscopy was employed to study Pin1 dynamics.
• Analysis focused on changes in intra- and inter-domain mobility upon substrate binding.

Main Results:

• Substrate binding to the Pin1 WW domain was observed to alter both intra- and inter-domain mobility.
• These changes in mobility were found to affect the catalytic activity of the distal PPIase domain.
• Results support the concept of dynamic allostery in Pin1 function.

Conclusions:

• Pin1 demonstrates dynamic allostery, where substrate binding allosterically modulates activity through conformational changes.
• A model of conformational selection is proposed to explain the observed interdomain communication in Pin1.