title: VAPB interacts with the mitochondrial protein PTPIP51 to regulate calcium homeostasis.
abstract: A proline to serine substitution at position 56 in the gene encoding vesicle-associated membrane protein-associated protein B (VAPB) causes some dominantly inherited familial forms of motor neuron disease including amyotrophic lateral sclerosis (ALS) type-8. VAPB is an integral endoplasmic reticulum (ER) protein whose amino-terminus projects into the cytosol. Overexpression of ALS mutant VAPBP56S disrupts ER structure but the mechanisms by which it induces disease are not properly understood. Here we show that VAPB interacts with the outer mitochondrial membrane protein, protein tyrosine phosphatase-interacting protein 51 (PTPIP51). ER and mitochondria are both stores for intracellular calcium (Ca(2+)) and Ca(2+) exchange between these organelles occurs at regions of ER that are closely apposed to mitochondria. These are termed mitochondria-associated membranes (MAM). We demonstrate that VAPB is a MAM protein and that loss of either VAPB or PTPIP51 perturbs uptake of Ca(2+) by mitochondria following release from ER stores. Finally, we demonstrate that VAPBP56S has altered binding to PTPIP51 and increases Ca(2+) uptake by mitochondria following release from ER stores. Damage to ER, mitochondria and Ca(2+) homeostasis are all seen in ALS and we discuss the implications of our findings in this context.
authors: Department of Neuroscience, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King’s College London, London SE5 8AF, UK. kurt.de_vos@kcl.ac.uk
authors: Kurt J
authors: KJ
authors: De Vos
authors: Gábor M
authors: GM
authors: Mórotz
authors: Radu
authors: R
authors: Stoica
authors: Elizabeth L
authors: EL
authors: Tudor
authors: Kwok-Fai
authors: KF
authors: Lau
authors: Steven
authors: S
authors: Ackerley
authors: Alice
authors: A
authors: Warley
authors: Christopher E
authors: CE
authors: Shaw
authors: Christopher C J
authors: CC
authors: Miller
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D020798:Two-Hybrid System Techniques; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D024101:Mitochondrial Proteins; C496748:VAPB protein, human; D033921:Vesicular Transport Proteins; D017027:Protein Tyrosine Phosphatases; C515449:RMDN3 protein, human; D002118:Calcium