title: Critical residues involved in tau binding to fyn: implications for tau phosphorylation in Alzheimer's disease.
abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by neuropathological deposits of amyloid plaques and neurofibrillary tangles comprised of β-amyloid and tau protein, respectively. In AD, tau becomes abnormally phosphorylated and aggregates to form intracellular deposits. However, the mechanisms by which tau exerts neurotoxicity in disease remain unclear. Recent studies have suggested that the presence of tau at synapses may indicate a role in neuronal signalling, which could be disrupted in pathological conditions. The non-receptor-associated tyrosine kinase fyn is located at the dendrite in neurons, where it was recently shown to interact with tau to stabilise receptor complexes at the post-synaptic density. Fyn also co-localises with tau in a proportion of neurons containing tau tangles in AD and fyn is also a tau kinase. Hence, tau-fyn interactions could play a pathogenic role in AD. Here we report the identification of critical proline residues, Pro213, Pro216, and Pro219, located within the fifth and sixth Pro-X-X-Pro motifs in the proline-rich region of tau, that are important for its binding to fyn. These residues in tau are flanked by numerous phosphorylation sites and therefore we investigated the relationship between fyn and the degree of tau phosphorylation in human post-mortem brain tissue. We found no difference in the amount of fyn present in control and AD brain. Notably, however, there was a significant correlation between fyn and phosphorylated tau at specific phospho-epitopes in control, but not in AD brain. Our results suggest that the pathological mechanisms underlying AD, that result in increased tau phosphorylation, may disrupt the physiological relationship between tau phosphorylation and fyn.
authors.affiliation: Department of Basic and Clinical Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute (K1.24), 125 Coldharbour Lane, London, SE5 9NU, UK.
authors.forename: Dawn H W
authors.initials: DH
authors.lastname: Lau
authors.affiliation: Department of Basic and Clinical Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute (K1.24), 125 Coldharbour Lane, London, SE5 9NU, UK.
authors.forename: Marte
authors.initials: M
authors.lastname: Hogseth
authors.affiliation: Department of Basic and Clinical Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute (K1.24), 125 Coldharbour Lane, London, SE5 9NU, UK.
authors.forename: Emma C
authors.initials: EC
authors.lastname: Phillips
authors.affiliation: Eli Lilly and Company Limited, Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey, GU20 6PH, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: O'Neill
authors.affiliation: Department of Basic and Clinical Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute (K1.24), 125 Coldharbour Lane, London, SE5 9NU, UK.|Present address: Nestlé Institute of Health Sciences, Lausanne, Switzerland.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Pooler
authors.affiliation: Department of Basic and Clinical Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute (K1.24), 125 Coldharbour Lane, London, SE5 9NU, UK.
authors.forename: Wendy
authors.initials: W
authors.lastname: Noble
authors.affiliation: Department of Basic and Clinical Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute (K1.24), 125 Coldharbour Lane, London, SE5 9NU, UK. diane.hanger@kcl.ac.uk.
authors.forename: Diane P
authors.initials: DP
authors.lastname: Hanger
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D020816:Amino Acid Motifs; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016466:CHO Cells; D003412:Cricetulus; D004926:Escherichia coli; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D011485:Protein Binding; D000072417:Protein Domains; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins; D051076:Proto-Oncogene Proteins c-fyn
keywords: Alzheimer’s disease; Fyn; PXXP motif; Phosphorylation; SH3; Tau