Comprehensive Atlas of the Myelin Basic Protein Interaction Landscape

Abstract

Intrinsically disordered myelin basic protein (MBP) is one of the key autoantigens in autoimmune neurodegeneration and multiple sclerosis particularly. MBP is highly positively charged and lacks distinct structure in solution and therefore its intracellular partners are still mostly enigmatic. Here we used combination of formaldehyde-induced cross-linking followed by immunoprecipitation and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to elucidate the interaction network of MBP in mammalian cells and provide the list of potential MBP interacting proteins. Our data suggest that the largest group of MBP-interacting proteins belongs to cellular proteins involved in the protein translation machinery, as well as in the spatial and temporal regulation of translation. MBP interacts with core ribosomal proteins, RNA helicase Ddx28 and RNA-binding proteins STAU1, TDP-43, ADAR-1 and hnRNP A0, which are involved in various stages of RNA biogenesis and processing, including specific maintaining MBP-coding mRNA. Among MBP partners we identified CTNND1, which has previously been shown to be necessary for myelinating Schwann cells for cell-cell interactions and the formation of a normal myelin sheath. MBP binds proteins MAGEB2/D2 associated with neurotrophin receptor p75NTR, involved in pathways that promote neuronal survival and neuronal death. Finally, we observed that MBP interacts with RNF40–a component of heterotetrameric Rnf40/Rnf20 E3 ligase complex, recruited by Egr2, which is the central transcriptional regulator of peripheral myelination. Concluding, our data suggest that MBP may be more actively involved in myelination not only as a main building block but also as a self-regulating element.

Overview of myelin, major myelin lipids, and myelin-associated proteins

“…A cholesterol content of 44% in myelin yields the most thermodynamically favorable MBP interaction and is optimal for membrane compaction and thermodynamic stability ( Träger et al, 2020 ). In addition to its structural importance– via interactions with lipids and myelin membrane-associated proteins–MBP also interacts with a large group of proteins related to protein expression and may play a regulatory role in myelinogenesis ( Smirnova et al, 2021 ).…”

Neurodegenerative Disorder Risk in Krabbe Disease Carriers

“…MBP is a highly abundant and essential membrane stacker in CNS and PNS myelin [ 59 ]. Smirnova et al [ 60 ] have recently delineated the wide interatomic pattern of MBP, which reveals an incredible, heterogeneous, and complex plethora of functions in which this intrinsically disordered protein may act. Among others, the MBP-interacting net includes cytoskeleton components and proteins involved in the reorganization of the actin cytoskeleton at the plasma membrane and cell adhesions [ 60 ].…”

“…Smirnova et al [ 60 ] have recently delineated the wide interatomic pattern of MBP, which reveals an incredible, heterogeneous, and complex plethora of functions in which this intrinsically disordered protein may act. Among others, the MBP-interacting net includes cytoskeleton components and proteins involved in the reorganization of the actin cytoskeleton at the plasma membrane and cell adhesions [ 60 ]. By linking the underling cytoskeleton and proteins containing SH3 domains to the membrane, it is also active in transmembrane signal transduction to the cytosol and, consequently, in myelinating cell response control [ 61 ].…”

Identification of potential regulatory long non-coding RNA-associated competing endogenous RNA axes in periplaque regions in multiple sclerosis

“…By altering Rho GTPase activity, CTNND1 is implicated in the regulation of cadherin-mediated adhesion and dynamic regulation of the actin cytoskeleton ( Anastasiadis et al, 2000 ; Noren et al, 2000 ; Grosheva et al, 2001 ). CTNND1 was found among myelin basic protein (MBP) partners by Smirnova et al (2021 ). Intrinsically aberrant MBP is one of the most important autoantigens in autoimmune neurodegeneration and MS ( Benjamins and Morell, 1978 ; Garbay et al, 1988 ).…”