[Seminar] Molecular details of two allosteric activation mechanisms: mRNA methyltransferase RNMT and E3 ubiquitin ligase Parkin

Seminar

Title: Molecular details of two allosteric activation mechanisms: mRNA methyltransferase RNMT and E3 ubiquitin ligase Parkin

Speaker: Andrei Pisliakov

Affiliation: School of Life Sciences & School of Science and Engineering, University of Dundee, UK

Host: António Baptista, Molecular Simulation

Abstract:

In this talk I will present two examples of our recent computational studies that have provided molecular insights into allosteric activation mechanisms of two important human enzymes.

RNA guanine-7 methyltransferase (RNMT) is one of the key enzymes in the mRNA "capping" process, during which a cap structure is added to the 5' end of mRNA transcripts. This step is critical for gene expression, being required for transcript processing and translation initiation. From biochemical studies it was known that human RNMT is regulated by a small protein RAM.  Through molecular dynamics and accelerated MD simulations, performed using the first crystal structure of the human RNMT-RAM complex, we have revealed the molecular mechanism of this allosteric regulation. We have also explained the cooperative binding effect of two ligands - GpppG cap and S-adenosyl methionine - in the RNMT active site.

Parkin is a RING-in-between-RING (RBR) E3-ubiquitin ligase involved in the control of mitophagy (mitochondrial autophagy). Upon activation, Parkin mediates the transfer of ubiquitin from a ubiquitin-conjugating enzyme (E2) to specific substrate proteins, labelling those for degradation.  Mutations of the Parkin gene are associated with autosomal recessive juvenile Parkinsonism (ARJP). Recent biochemical and structural data suggested that several distinct factors are involved in Parkin activation.  However, a coherent picture of this process has not yet emerged. By using a combination of computational methods, we systematically re-examined the role of various structural and biochemical factors on Parkin stability, conformational dynamics, and initial steps of activation. Our findings starkly contrast several popular proposals existing in the Parkin field.  Our results offer novel molecular perspectives into activation mechanism of Parkin as well as a guidance for future experi  mental studies.