title: VAPB interacts with and modulates the activity of ATF6.
abstract: A mis-sense point mutation in the human VAPB gene is associated with a familial form of motor neuron disease that has been classified as Amyotrophic Lateral Sclerosis type VIII. Affected individuals suffer from a spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) or an atypical slowly progressing form of ALS. Mammals have two homologous VAP genes, vapA and vapB. VAPA and VAPB share 76% similar or identical amino acid residues; both are COOH-terminally anchored membrane proteins enriched on the endoplasmic reticulum. Several functions have been ascribed to VAP proteins including membrane trafficking, cytoskeleton association and membrane docking interactions for cytoplasmic factors. It is shown here that VAPA and VAPB are expressed in tissues throughout the body but at different levels, and that they are present in overlapping but distinct regions of the endoplasmic reticulum. The disease-associated mutation in VAPB, VAPB(P56S), lies within a highly conserved N-terminal region of the protein that shares extensive structural homology with the major sperm protein (MSP) from nematodes. The MSP domain of VAPA and VAPB is found to interact with the ER-localized transcription factor ATF6. Over expression of VAPB or VAPB(P56S) attenuates the activity of ATF6-regulated transcription and the mutant protein VAPB(P56S) appears to be a more potent inhibitor of ATF6 activity. These data indicate that VAP proteins interact directly with components of ER homeostatic and stress signalling systems and may therefore be parts of a previously unidentified regulatory pathway. The mis-function of such regulatory systems may contribute to the pathological mechanisms of degenerative motor neuron disease.
authors.affiliation: The Centre for Neuroscience Research, The University of Edinburgh, The Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK. paul.skehel@ed.ac.uk
authors.forename: Christos
authors.initials: C
authors.lastname: Gkogkas
authors.forename: Susan
authors.initials: S
authors.lastname: Middleton
authors.forename: Anna M
authors.initials: AM
authors.lastname: Kremer
authors.forename: Caroline
authors.initials: C
authors.lastname: Wardrope
authors.forename: Matthew
authors.initials: M
authors.lastname: Hannah
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Gillingwater
authors.forename: Paul
authors.initials: P
authors.lastname: Skehel
mesh_terms: D051702:Activating Transcription Factor 6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D017434:Protein Structure, Tertiary / Q000235:genetics; D051381:Rats; D014018:Tissue Distribution; D014158:Transcription, Genetic; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051702:Activating Transcription Factor 6; D002352:Carrier Proteins; D008565:Membrane Proteins; C496748:VAPB protein, human; C529892:VAPB protein, mouse; C491920:Vapa protein, mouse; C491919:Vapa protein, rat; D033921:Vesicular Transport Proteins