Biophysical and functional characterization of hippocalcin mutants responsible for human dystonia

Helassa, N ORCID: 0000-0003-3743-1886, Antonyuk, SV ORCID: 0000-0002-2779-9946, Lian, L-Y, Haynes, LP ORCID: 0000-0002-1296-0338 and Burgoyne, RD ORCID: 0000-0002-9219-0387 (2017) Biophysical and functional characterization of hippocalcin mutants responsible for human dystonia. Human molecular genetics, 26 (13). pp. 2426-2435.

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Abstract

Dystonia is a neurological movement disorder that forces the body into twisting, repetitive movements or sometimes painful abnormal postures. With the advent of next-generation sequencing technologies, the homozygous mutations T71N and A190T in the neuronal calcium sensor (NCS) hippocalcin were identified as the genetic cause of primary isolated dystonia (DYT2 dystonia). However, the effect of these mutations on the physiological role of hippocalcin has not yet been elucidated. Using a multidisciplinary approach, we demonstrated that hippocalcin oligomerises in a calcium-dependent manner and binds to voltage-gated calcium channels. Mutations T71N and A190T in hippocalcin did not affect stability, calcium-binding affinity or translocation to cellular membranes (Ca2+/myristoyl switch). We obtained the first crystal structure of hippocalcin and alignment with other NCS proteins showed significant variability in the orientation of the C-terminal part of the molecule, the region expected to be important for target binding. We demonstrated that the disease-causing mutations did not affect the structure of the protein, however both mutants showed a defect in oligomerisation. In addition, we observed an increased calcium influx in KCl-depolarised cells expressing mutated hippocalcin, mostly driven by N-type voltage-gated calcium channels. Our data demonstrate that the dystonia-causing mutations strongly affect hippocalcin cellular functions which suggest a central role for perturbed calcium signalling in DYT2 dystonia.

Item Type:	Article
Uncontrolled Keywords:	Mutation, Calcium, Dystonia, Biophysics, Calcium signaling, Homozygote, Tissue membrane, Movement disorders, Pain, Potassium chloride, Technology, Translocation (genetics), Posture, Voltage gated calcium channel, Affinity, Sensor, Massively-parallel genome sequencing, Binding (molecular function), Crystal structure, Molecule
Depositing User:	Symplectic Admin
Date Deposited:	05 Jun 2018 09:35
Last Modified:	19 Jan 2023 01:32
DOI:	10.1093/hmg/ddx133
Open Access URL:	https://doi.org/10.1093/hmg/ddx133
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3022103

Available Versions of this Item

• Biophysical and functional characterization of hippocalcin mutants responsible for human dystonia. (deposited 21 Apr 2017 13:34)
  • Biophysical and functional characterization of hippocalcin mutants responsible for human dystonia. (deposited 26 Jul 2017 11:19)
    • Biophysical and functional characterization of hippocalcin mutants responsible for human dystonia. (deposited 01 Aug 2017 08:36)
      • Biophysical and functional characterization of hippocalcin mutants responsible for human dystonia. (deposited 05 Jun 2018 09:35) [Currently Displayed]