Premium
Endoproteolytic processing of the mammalian prion glycoprotein family
Author(s) -
Mays Charles E.,
Coomaraswamy Janaky,
Watts Joel C.,
Yang Jing,
Ko Kerry W.S.,
Strome Bob,
Mercer Robert C.C.,
Wohlgemuth Serene L.,
SchmittUlms Gerold,
Westaway David
Publication year - 2014
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12654
Subject(s) - cleavage (geology) , proteases , proteolysis , biology , glycoprotein , mutant , glycosylation , scrapie , in vitro , cleavage factor , in vivo , biochemistry , chemistry , prion protein , genetics , gene , medicine , paleontology , disease , pathology , fracture (geology) , messenger rna , enzyme
Cellular prion protein ( P r P C ) misfolds to form infectivity‐associated scrapie prion protein and generates C ‐terminal fragments C 1 and C 2 in healthy and prion‐infected animals. C1 cleavage occurs N ‐terminally of P r P C 's hydrophobic domain, whereas the larger C 2 fragment is generated by cleavage at the end of the octarepeat region. As the PrP‐like proteins D oppel and S hadoo ( S ho) have been reported to inhabit similar membrane environments as P r P C , we investigated endoproteolysis by using a panel of mutant alleles. Doppel undergoes efficient in vivo cleavage at a C 1 site mapped to the start of the globular domain, which is a structurally similar cleavage site to that in P r P C . Sho is processed to C 1 and C 2 fragments, and proved refractory to mutagenesis to inactivate C 1 cleavage. As a reciprocal product of C 1 cleavage, Sho also engenders a metabolically stable N 1 fragment with a C ‐terminus after its hydrophobic domain, an observation that may account for N 1's association with membrane and/or cellular fractions in vitro and in vivo . Our data indicate that glycosylation status and yet to be identified proteases modulate internal C 1 and C 2 proteolysis events within the mammalian prion protein family.