Phosphorylation by PINK1 Releases the UBL Domain and Initializes the Conformational Opening of the E3 Ubiquitin Ligase Parkin
Figure 4
MdMD excursions along the pathway of the UBL domain across Parkin.
Representative pathways via MdMD excursions between LC-MOD/MC generated conformers for the movement of the N-terminal region (residues 1–140) in MDS state 1 (panel A) to the active site region in MDS state 5 (panel E). Panels A–E and A′–E′ represent the five key points from the guideposts that MdMD was able to drive the structures toward. RMSD between the structural model and the guideposts were within 3 Å in each case. Color-coded ribbon structures are given. A) The initial structure for Parkin is mostly unperturbed after 3 ns of MdMD sampling with global variable based on LCMOD sampling between generated Parkin conformers. B) Opening of the N-terminal region is shown after>10 ns of MdMD sampling. C) Midpoint for the UBL domain movement towards the active site region following>15 ns of MdMD sampling. The linker helix region is more dynamic, exposing the E2 binding site in RING1. D) UBL domain adjustment as it approaches the C-terminal region after 30 ns of MdMD sampling. E) The UBL domain is in final position and occupies region around the active site (Cys431) after 35 ns of MdMD sampling. A′–E′) Superposition of the four replicates from MdMD that match the relative time point/stage from panels A–E. Ensemble of structures from replicates gives a common relative pathway between guideposts generated conformers.