Class I major histocompatibility complex, the trojan horse for secretion of amyloidogenic β2-microglobulin.

The Journal of Biological Chemistry
Levon HalabelianV Bellotti

Abstract

To form extracellular aggregates, amyloidogenic proteins bypass the intracellular quality control, which normally targets unfolded/aggregated polypeptides. Human D76N β2-microglobulin (β2m) variant is the prototype of unstable and amyloidogenic protein that forms abundant extracellular fibrillar deposits. Here we focus on the role of the class I major histocompatibility complex (MHCI) in the intracellular stabilization of D76N β2m. Using biophysical and structural approaches, we show that the MHCI containing D76N β2m (MHCI76) displays stability, dissociation patterns, and crystal structure comparable with those of the MHCI with wild type β2m. Conversely, limited proteolysis experiments show a reduced protease susceptibility for D76N β2m within the MHCI76 as compared with the free variant, suggesting that the MHCI has a chaperone-like activity in preventing D76N β2m degradation within the cell. Accordingly, D76N β2m is normally assembled in the MHCI and circulates as free plasma species in a transgenic mouse model.

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Citations

Oct 18, 2014·Nature Chemical Biology·Anne GershensonSheena E Radford
Jun 1, 2016·Frontiers in Molecular Biosciences·Robert KisilevskyVittorio Bellotti
Apr 25, 2017·Amyloid : the International Journal of Experimental and Clinical Investigation : the Official Journal of the International Society of Amyloidosis·Matteo de RosaStefano Ricagno
Feb 16, 2021·Journal of the American Society for Mass Spectrometry·Owen CornwellAlison E Ashcroft

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Methods Mentioned

BETA
circular dichroism
transgenic
size exclusion chromatography
static light scattering
PCR
NMR
FACS

Software Mentioned

CCP4MG
COOT ( Crystallographic Object - Oriented Toolkit )
refine
Xtriage
PHASER
Phenix
REFMAC5

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