Steric interference from intrinsically disordered regions controls dynamin-related protein 1 self-assembly during mitochondrial fission

Scientific Reports
Bin LuRajesh Ramachandran

Abstract

The self-assembling, mechanoenzymatic dynamin superfamily GTPase, dynamin-related protein 1 (Drp1), catalyzes mitochondrial and peroxisomal fission. Distinct intrinsically disordered regions (IDRs) in Drp1 substitute for the canonical pleckstrin homology (PH) domain and proline-rich domain (PRD) of prototypical dynamin, which cooperatively regulate endocytic vesicle scission. Whether the Drp1 IDRs function analogously to the corresponding dynamin domains however remains unknown. We show that an IDR unique to the Drp1 GTPase (G) domain, the 'extended 80-loop', albeit dissimilar in location, structure, and mechanism, functions akin to the dynamin PRD by enabling stable Drp1 mitochondrial recruitment and by suppressing Drp1 cooperative GTPase activity in the absence of specific partner-protein interactions. Correspondingly, we find that another IDR, the Drp1 variable domain (VD), in conjunction with the conserved stalk L1N loop, functions akin to the dynamin PH domain; first, in an 'auto-inhibitory' capacity that restricts Drp1 activity through a long-range steric inhibition of helical inter-rung G-domain dimerization, and second, as a 'fulcrum' for Drp1 self-assembly in the proper helical register. We show that the Drp1 VD is nec...Continue Reading

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Citations

Nov 1, 2018·Molecular Biology of the Cell·Ehsan IrajizadAshutosh Agrawal
Jul 29, 2019·Mitochondrion·Ashutosh Agrawal, Rajesh Ramachandran
Nov 7, 2020·Biochemical Society Transactions·Jasmine CornishHelen R Mott
Jun 1, 2020·Pharmacology & Therapeutics·Ayeshah A RosdahShiang Y Lim
Mar 21, 2021·FEBS Letters·Nethmi M B YapaMichael T Ryan
Jul 16, 2021·Proceedings of the National Academy of Sciences of the United States of America·Mukesh MahajanRajesh Ramachandran

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Methods Mentioned

BETA
GTPases
GTPase
fluorescence imaging
size-exclusion
light scattering
X-ray
dynamic light scattering
FRET
isothermal titration calorimetry
sumoylation

Software Mentioned

PSIPRED
Origin®
Dynamics

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