Characterization of p56S insoluble aggregates. Analysis of the solubilization of the indicated mutants suggest that the oligomerization of VAP-B(P56S) is mediated mainly by the coiled-coil domain and that the GXXXG also contributes to VAP-B(P56S) oligomerization and consequently for the production… Continue Reading
Oligomerization of VAP-B(P56S) prevents binding of FFAT proteins. We found that the conformational changes of MSP domain of P56S mutant have no direct effect on FFAT-binding. Rather, they enhance VAP-B(P56S) oligomerization driven by the combined contributions of the coiled-coil and… Continue Reading
The P56S mutation induces the exposure of hydrophobic patches, thereby facilitating MSP oligomerization. To better understand how the P56S mutation enhances oligomerization of VAP-B(P56S), we characterized the folding properties of recombinant purified MSP domains of the WT and P56S mutant,… Continue Reading
The N-terminal cytoplasmic MSP (major sperm protein) domain of VAP-B consistes of 125 amino acids (aa), and a coiled-coil domain (CCD) of ~50 aa. Proline 56 resides within a highly conserved sequence of 16 aa in the MSP domain in… Continue Reading
We defined the structural requirements for VAP-B oligomerization and demonstrated their contribution for VAP-B(P56S) aggregation and neurotoxicity. We show that the oligomerization of VAP-B is mainly mediated by its coiled-coil domain, and that the GXXXG dimerization motif within the transmembrane… Continue Reading
Potential mechanisms underlying the aggregation and motor neurodegeneration of VAP-B (P56S) mutant.
Expression of the VAP-B(P56S) mutant in cultured cells results in the formation of insoluble protein aggregates. These aggregates might induce loss-of-function of wild-type VAP-B protein, gain of toxic function, or both.
The VAP-B is an integral endoplasmic reticulum (ER)-membrane protein implicated in the regulation of a wide range of cellular processes, including membrane trafficking, lipid transport and metabolism, and the unfolded protein response. In 2004, a dominant missense mutation (P56S) within the human VAP-Bgene… Continue Reading
Amyotrophic lateral sclerosis (ALS) is a motor neurone disease (MND) characterized by death of motor neurons in the cerebral cortex, brain stem, and spinal cord. ALS is one of the most common adult motor neuron diseases that, at present, has no cure or effective… Continue Reading
The VAPs (VAMP-associated proteins) are highly conserved integral endoplasmic reticulum (ER)-membrane proteins, implicated in diverse cellular functions, including regulation of lipid transport and homeostasis, membrane trafficking, neurotransmitter release, stabilization of presynaptic microtubules, and the unfolded protein response (UPR). A single… Continue Reading
