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Human Miro Proteins Act as NTP Hydrolases through a Novel, Non-Canonical Catalytic Mechanism. | LitMetric

Human Miro Proteins Act as NTP Hydrolases through a Novel, Non-Canonical Catalytic Mechanism.

Int J Mol Sci

Department of Applied Sciences Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne NE1 8ST, UK.

Published: December 2018

AI Article Synopsis

  • - Mitochondria are important organelles involved in energy production, calcium balance, and cell death, with Miro proteins playing a key role in their transport and function.
  • - Human Miro proteins, despite missing key residues typically found in GTPases, were found to exhibit GTPase activity and also show the ability to bind various substrates.
  • - Structural studies suggest that Miros utilize a unique mechanism for catalysis, involving an "internal arginine finger" that allows them to function without the traditional GTPase-activating proteins (GAPs).

Article Abstract

Mitochondria are highly dynamic organelles that play a central role in multiple cellular processes, including energy metabolism, calcium homeostasis and apoptosis. Miro proteins (Miros) are "atypical" Ras superfamily GTPases that display unique domain architecture and subcellular localisation regulating mitochondrial transport, autophagy and calcium sensing. Here, we present systematic catalytic domain characterisation and structural analyses of human Miros. Despite lacking key conserved catalytic residues (equivalent to Ras Y32, T35, G60 and Q61), the Miro N-terminal GTPase domains display GTPase activity. Surprisingly, the C-terminal GTPase domains previously assumed to be "relic" domains were also active. Moreover, Miros show substrate promiscuity and function as NTPases. Molecular docking and structural analyses of Miros revealed unusual features in the Switch I and II regions, facilitating promiscuous substrate binding and suggesting the usage of a novel hydrolytic mechanism. The key substitution in position 13 in the Miros leads us to suggest the existence of an "internal arginine finger", allowing an unusual catalytic mechanism that does not require GAP protein. Together, the data presented here indicate novel catalytic functions of human Miro atypical GTPases through altered catalytic mechanisms.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321465PMC
http://dx.doi.org/10.3390/ijms19123839DOI Listing

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