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

Meiling Zhang, Thomas E. Frederick, Jamie VanPelt, David A. Case, Jeffrey W. Peng

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

The functional mechanisms of multidomain proteins often exploit interdomain interactions, or "cross-talk." An example is human Pin1, an essential mitotic regulator consisting of a Trp- Trp(WW) domain flexibly tethered to a peptidyl-prolyl isomerase (PPIase) domain, resulting in interdomain interactions important for Pin1 function. Substrate binding to theWWdomain alters its transient contacts with the PPIase domain via means that are only partially understood. Accordingly, we have investigated Pin1 interdomain interactions using NMR paramagnetic relaxation enhancement (PRE) and molecular dynamics (MD) simulations. The PREs show that apo-Pin1 samples interdomain contacts beyond the range suggested by previous structural studies. They further show that substrate binding to the WW domain simultaneously alters interdomain separation and the internal conformation of the WW domain. A 4.5-ms all-atom MD simulation of apo-Pin1 suggests that the fluctuations of interdomain distances are correlated with fluctuations of WW domain interresidue contacts involved in substrate binding. Thus, the interdomain/WWdomain conformations sampled by apo-Pin1 may already include a range of conformations appropriate for binding Pin1's numerous substrates. The proposed coupling between intra-/interdomain conformational fluctuations is a consequence of the dynamic modular architecture of Pin1. Such modular architecture is common among cell-cycle proteins; thus, theWW-PPIase domain cross-talk mechanisms of Pin1 may be relevant for their mechanisms as well.

Original languageEnglish (US)
Pages (from-to)16585-16603
Number of pages19
JournalJournal of Biological Chemistry
Volume295
Issue number49
DOIs
StatePublished - Dec 4 2020

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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