The intrinsically disordered protein glue of the myelin major dense line: Linking AlphaFold2 predictions to experimental data

Krokengen, Oda C.; Raasakka, Arne; Kursula, Petri

doi:10.1016/j.bbrep.2023.101474

Cited by 2 publications

(4 citation statements)

References 102 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…An AlphaFold2 (Jumper et al, 2021) model for hP0 was generated as well as a 3D reconstruction of the electron density from the experimental SAXS data. SEC-SAXS data were also acquired for highly concentrated, pure P0ct (Supplementary Figure 5) to supplement the findings; an AlphaFold2 model of P0ct has been discussed before (Krokengen et al, 2023). P0ct was elongated and flexible, showing a mixture of more extended and compacted conformations (Supplementary Figure 5).…”

Section: Resultsmentioning

confidence: 96%

“…The Ig-like domain of P0 has been crystallized and characterized at high resolution (Liu et al, 2012; Shapiro et al, 1996), while biophysical characterization has been done for P0ct (Krokengen et al, 2023; Luo et al, 2007; Raasakka et al, 2019a; Raasakka et al, 2019b; Raasakka et al, 2019c). Consequently, this key protein of PNS myelin has only been studied in parts, and no experimental information on full-length P0 exists, apart from low-resolution electron cryomicrographs of liposome-reconstituted P0 purified from bovine nerves and reconstituted into liposomes (Raasakka et al, 2019c).…”

Section: Resultsmentioning

confidence: 99%

“…A part of the long helix in the AlphaFold2 model (Figure 5D, black dotted square) belongs to P0ct. In fact, an amphipathic helix is believed to be separated from the TM helix by a small hinge necessary for its flexibility to bind alongside the membrane surface (D’Urso et al, 1990; Krokengen et al, 2023). When P0ct is given as a single sequence, AlphaFold2 models P0ct to contain helical segments (Krokengen et al, 2023), which has been observed experimentally when bound to lipid membranes (Raasakka et al, 2019a; Raasakka et al, 2019b; Raasakka et al, 2019c).…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

The cytoplasmic tail of myelin protein zero induces morphological changes in lipid membranes

Krokengen,

Touma,

Mularski

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

The major myelin protein expressed by the peripheral nervous system Schwann cells is protein zero (P0), representing 50% of the total protein content in myelin. This 30-kDa integral membrane protein consists of an immunoglobulin (Ig)-like domain, a transmembrane helix, and a 69-residue C-terminal cytoplasmic tail (P0ct). The basic residues in P0ct contribute to the tight packing of the myelin lipid bilayers, and alterations in the tail affect how P0 functions as an adhesion molecule necessary for the stability of compact myelin. Several neurodegenerative neuropathies are related to P0, including the more common Charcot-Marie-Tooth disease (CMT) and Dejerine-Sottas syndrome (DSS), but also rare cases of motor and sensory polyneuropathy. We find that high P0ct concentrations affect the membrane properties of bicelles and induce a lamellar-to-inverted hexagonal phase transition, which causes the bicelles to fuse into long, protein-containing filament-like structures. These structures likely reflect the formation of semi-crystalline lipid domains of potential relevance for myelination. Not only is P0ct important for stacking lipid membranes, but time-lapse fluorescence microscopy shows that it might affect membrane properties during myelination. We further describe recombinant production and low-resolution structural characterization of full-length human P0. Our findings shed light on P0ct effects on membrane properties, and with successful purification of full-length P0, we have new tools to study in vitro the role P0 has in myelin formation and maintenance.

show abstract

Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The cytoplasmic tail of myelin protein zero induces morphological changes in lipid membranes

Krokengen,

Touma,

Mularski

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Accordingly, a common denominator for P0ct, P2, and MBP is that they all reside within the MDL of PNS compact myelin. Both P0ct [7,10,11,[36][37][38][39][40][41][42], MBP [20,23,37,38,[43][44][45][46][47][48], and P2 [26,27,32,33,35,[49][50][51] have been studied separately with respect to their structure and membrane interactions, while their effects on lipid membranes together have received little attention. A few studies have pursued myelin protein-protein associations: P0 with myelin protein 22 (PMP22) [52,53], MBP and P2 [54], PMP22 with calnexin [55], L-periaxin and dystrophinrelated protein [56] as well as β4 integrin [57], and 2′,3′-cyclic nucleotide 3′phosphodiesterase (CNPase) with actin [58,59].…”

Section: Introductionmentioning

confidence: 99%

On the synergy between myelin proteins P0, MBP, and P2 in peripheral nerve major dense line formation

Krokengen,

Raasakka,

Klenow

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Myelin is a proteolipid membrane multilayer held together by a set of proteins. The proper formation and function of the myelin sheath relies on the coordinated action of several key myelin proteins. Research exploring how proteins from the peripheral myelin cytoplasmic apposition – myelin basic protein (MBP), the cytoplasmic tail of myelin protein zero (P0ct), and peripheral myelin protein 2 (P2) – interact with each other and with myelin-like membranes was conducted using various techniques, such as small-angle X-ray diffraction (SAXD), differential scanning calorimetry (DSC), surface plasmon resonance (SPR), as well as electron and live epifluorescence microscopy. DSC revealed changes in lipid interactions depending on the protein combination, with MBP and P0ct binding more tightly to lipid membranes than P2, resulting in altered membrane fluidity and stability. These results were supported by SPR, which indicated that the myelin proteins may compete for membrane surface binding. Analysis of the Bragg peaks induced by the myelin proteins in lipidic environments showed both lamellar and non-lamellar phases in protein-lipid complexes. The results indicate both synergy and competition between the three main proteins residing in the PNS myelin major dense line. Furthermore, the observed direct effects of myelin proteins on lipid membrane properties may be relevant to their function in myelinating cells.

show abstract

The intrinsically disordered protein glue of the myelin major dense line: Linking AlphaFold2 predictions to experimental data

Cited by 2 publications

References 102 publications

The cytoplasmic tail of myelin protein zero induces morphological changes in lipid membranes

The cytoplasmic tail of myelin protein zero induces morphological changes in lipid membranes

On the synergy between myelin proteins P0, MBP, and P2 in peripheral nerve major dense line formation

Contact Info

Product

Resources

About