All together now: molecular mechanism of the myelin inhibitors at the membrane

Samenvatting

In the mammalian nervous system highly-abundant intercellular connections define basic brain functions such as learning and memory formation. Oligodendrocyte cells form dense layers of membrane, called myelin, around axons to enhance conductance velocity, and provide physical protection and metabolic support to neurons. Three cell-surface expressed proteins on myelin, the myelin inhibitors, interact with the receptor PirB on neurons to regulate nervous system development and function. Malfunction of these proteins, for example arising from mutations, causes demyelination and neurodegenerative disorders. Importantly, these proteins actively inhibit the regeneration of a central nervous system that has suffered damage from injury or disease. Interactions amongst the myelin inhibitors and PirB in cis (on the same cell) and trans (between cells) are critical to their function and controlled by their setting at and between cell membranes. Many other adhesion and intercellular signaling systems depend on similar multivalent interaction mechanisms to induce the formation of higher-order assemblies for their function. We will use the myelin inhibitors and PirB as a target system to dissect the mechanistic requirements of intercellular adhesion and signaling at and between cell membranes.

To bridge the gap between atomic-mechanistic and cellular-functional knowledge of intercellular adhesion and signaling of the myelin inhibitor system, we will use and develop experimental approaches to determine cis and trans multivalent interactions and to visualize higher-order assemblies formed between membrane surfaces with cryo-electron microscopy. We will combine this analysis with X-ray crystallography to resolve atomic structures and conformational rearrangements in the pre- and post-ligand bound state. This hybrid approach of studying proteins in increasingly complex settings; isolation, complexes, liposomes and cells, enables us to dovetail atomic-level structural insights with mechanistic information in cells. This will ultimately unravel the mechanisms of myelin inhibitor-controlled intercellular communication and impact on targeting neurological disorders and stimulating nervous system regeneration.

Kenmerken

Projectnummer

OCENW.KLEIN.026

Hoofdaanvrager

Dr. ir. B.J.C. Janssen

Verbonden aan

Universiteit Utrecht, Faculteit Bètawetenschappen, Departement Scheikunde

Looptijd

01/09/2019 tot 31/08/2023