Latent S49P neuroserpin forms polymers in the dementia familial encephalopathy with neuroserpin inclusion bodies.
The serpinopathies result from conformational transitions in members of the serine proteinase inhibitor superfamily with aberrant tissue deposition or loss of function. They are typified by mutants of neuroserpin that are retained within the endoplasmic reticulum of neurons as ordered polymers in association with dementia. We show here that the S49P mutant of neuroserpin that causes the dementia familial encephalopathy with neuroserpin inclusion bodies (FENIB) forms a latent species in vitro and in vivo in addition to the formation of polymers. Latent neuroserpin is thermostable and inactive as a proteinase inhibitor, but activity can be restored by refolding. Strikingly, latent S49P neuroserpin is unlike any other latent serine proteinase inhibitor (serpin) in that it spontaneously forms polymers under physiological conditions. These data provide an alternative method for the inactivation of mutant neuroserpin as a proteinase inhibitor in FENIB and demonstrate a second pathway for the formation of intracellular polymers in association with disease.
Onda
Maki
M
Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 2XY, United Kingdom. onda@center.osaka-wu.ac.jp
Belorgey
Didier
D
Sharp
Lynda K
LK
Lomas
David A
DA
D000328:Adult; D000818:Animals; D001704:Biopolymers / Q000737:chemistry* / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D019343:Citric Acid / Q000737:chemistry; D003704:Dementia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D002479:Inclusion Bodies / Q000737:chemistry*; D008875:Middle Aged; D008958:Models, Molecular; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009479:Neuropeptides / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D017354:Point Mutation; D011487:Protein Conformation; D017510:Protein Folding; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015843:Serpins / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D013696:Temperature; D000097522:Neuroserpin
D001704:Biopolymers; D019343:Citric Acid; D009479:Neuropeptides; D011994:Recombinant Proteins; D015843:Serpins; D000097522:Neuroserpin