5m6c | pdb_00005m6c

CRYSTAL STRUCTURE OF T71N MUTANT OF HUMAN HIPPOCALCIN

spinqualitylabelsall models 5m6c, resolution 3.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5m6c is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CA Gene: HPCA, BDR2 (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [HPCA_HUMAN] The disease is caused by mutations affecting the gene represented in this entry. Function [HPCA_HUMAN] May be involved in the calcium-dependent regulation of rhodopsin phosphorylation. Binds two calcium ions. Publication Abstract from PubMed 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. Biophysical and functional characterization of hippocalcin mutants responsible for human dystonia.,Helassa N, Antonyuk SV, Lian LY, Haynes LP, Burgoyne RD Hum Mol Genet. 2017 Apr 7. doi: 10.1093/hmg/ddx133. PMID:28398555 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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