The intracellular domain of major histocompatibility class-I proteins is essential for maintaining excitatory spine density and synaptic ultrastructure in the brain

Author:

Lazarczyk Maciej J.,Eyford Brett A.,Varghese Merina,Arora Hitesh,Munro Lonna,Warda Tahia,Pfeifer Cheryl G.,Sowa Allison,Dickstein Daniel R.,Rumbell Timothy,Jefferies Wilfred A.,Dickstein Dara L.

Abstract

AbstractMajor histocompatibility complex class I (MHC-I) proteins are expressed in neurons, where they regulate synaptic plasticity. However, the mechanisms by which MHC-I functions in the CNS remains unknown. Here we describe the first structural analysis of a MHC-I protein, to resolve underlying mechanisms that explains its function in the brain. We demonstrate that Y321F mutation of the conserved cytoplasmic tyrosine-based endocytosis motif YXXΦ in MHC-I affects spine density and synaptic structure without affecting neuronal complexity in the hippocampus, a region of the brain intimately involved in learning and memory. Furthermore, the impact of the Y321F substitution phenocopies MHC-I knock-out (null) animals, demonstrating that reverse, outside-in signalling events sensing the external environment is the major mechanism that conveys this information to the neuron and this has a previously undescribed yet essential role in the regulation of synaptic plasticity.

Publisher

Springer Science and Business Media LLC

Subject

Multidisciplinary

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