Prion protein “gamma-cleavage”: characterizing a novel endoproteolytic processing event

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• 作者：Victoria Lewis ; Vanessa A. Johanssen…
• 关键词：Prion protein ; Endoproteolysis ; Protein processing ; Protein cleavage
• 刊名：Cellular and Molecular Life Sciences (CMLS)
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：73
• 期：3
• 页码：667-683
• 全文大小：2,910 KB
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• 作者单位：Victoria Lewis (1)
  Vanessa A. Johanssen (2)
  Peter J. Crouch (2)
  Genevieve M. Klug (1) (3)
  Nigel M. Hooper (4)
  Steven J. Collins (1) (3)
  
  1. Department of Medicine, RMH, The University of Melbourne, Parkville, VIC, 3010, Australia
  2. Department of Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia
  3. The Australian National Creutzfeldt-Jakob Disease Registry, The University of Melbourne, Parkville, VIC, 3010, Australia
  4. Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, M13 9PT, UK
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Life Sciences
  Cell Biology
  Biomedicine
  Life Sciences
  Biochemistry
  
• 出版者：Birkh盲user Basel
• ISSN：1420-9071

文摘

The cellular prion protein (PrPC) is a ubiquitously expressed protein of currently unresolved but potentially diverse function. Of putative relevance to normal biological activity, PrPC is recognized to undergo both α- and β-endoproteolysis, producing the cleavage fragment pairs N1/C1 and N2/C2, respectively. Experimental evidence suggests the likelihood that these processing events serve differing cellular needs. Through the engineering of a C-terminal c-myc tag onto murine PrPC, as well as the selective use of a far-C-terminal anti-PrP antibody, we have identified a new PrPC fragment, nominally ‘C3’, and elaborating existing nomenclature, ‘γ-cleavage’ as the responsible proteolysis. Our studies indicate that this novel γ-cleavage event can occur during transit through the secretory pathway after exiting the endoplasmic reticulum, and after PrPC has reached the cell surface, by a matrix metalloprotease. We found that C3 is GPI-anchored like other C-terminal and full length PrPC species, though it does not localize primarily at the cell surface, and is preferentially cleaved from an unglycosylated substrate. Importantly, we observed that C3 exists in diverse cell types as well as mouse and human brain tissue, and of possible pathogenic significance, γ-cleavage may increase in human prion diseases. Given the likely relevance of PrPC processing to both its normal function, and susceptibility to prion disease, the potential importance of this previously underappreciated and overlooked cleavage event warrants further consideration. Keywords Prion protein Endoproteolysis Protein processing Protein cleavage