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

Peters, Daniel, Kay, Laura, Eswaran, Jeyanthy, Lakey, Jeremy and Soundararajan, Meera (2018) Human Miro Proteins Act as NTP Hydrolases through a Novel, Non-Canonical Catalytic Mechanism. International Journal of Molecular Sciences, 19 (12). p. 3839. ISSN 1422-0067

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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.

Item Type: Article
Subjects: C700 Molecular Biology, Biophysics and Biochemistry
Department: Faculties > Health and Life Sciences > Applied Sciences
Depositing User: Becky Skoyles
Date Deposited: 25 Jan 2019 09:41
Last Modified: 01 Aug 2021 07:35

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