[Frontiers in Bioscience 15, 1086-1104, June 1, 2010]

Copper, endoproteolytic processing of the prion protein and cell signalling

Cathryn Louise Haigh, Shai Y Marom, Steven John Collins

The Department of Pathology & Mental Health Research Institute, The University of Melbourne, Parkville, Victoria, Australia, 3010

TABLE OF CONTENTS

1. Abstract
2. Introduction
2. Introduction
3. PrPC and copper
3.1. Copper co-ordination by PrPC
3.2. Copper and PrPC function
3.3. PrP, copper and signal transduction
4. Cleavage of PrP
4.1. Characterisation of PrPC cleavage
4.1.1. Enzymatic mediators of alpha-cleavage
4.1.2. Mechanisms and locations of beta cleavage
4.2. Cell Signalling and PrPC cleavage
4.2.1. Signalling pathways leading to PrPC alpha-cleavage
4.2.1.1. PrPC signalling and alpha-cleavage
4.2.2. Linking PrPC cleavage and cell signalling
4.2.2.1. Cleavage and PrPC binding partners
4.3. Cleavage and prion transmissibility
5. PrPC, copper, cleavage and signalling
5.1. Copper and cleavage functioning as interacting contextual switches
5.2. PrP, acting as an ionophore, influences cleavage and function
5.3. Copper as a biosensor for cleavage fragment activation
5.4. PrPC regulation by cleavage products
6. Closing correlative remarks
7. Acknowledgments
8. References

1. ABSTRACT

Recently, understanding of many molecular interactions has progressed appreciably and cellular events once thought to be by-products of more important reactions or to be detrimental to cellular function are now known to be part of complex interactions of the cell with its environment.  Numerous proteins can elicit differing effects depending upon post-translational modification events such as complex glycosylation and endoproteolytic cleavage or through binding co-factors including metal ions; the prion protein (PrP) is likely one such example.  Its absolute requirement for pathogenesis has made the function of PrP an area of intense study but with apparently inconsistent results.  This may, in part, stem from the ability of PrP to undergo different modifications to varying extents depending upon precise cellular circumstances.  Specific modifications may promote altered association with binding partners resulting in apparent promiscuity of PrP interactions and activation of different signalling pathways, producing the diversity of functions suggested for this protein.  This review discusses how modification of PrP by internal cleavage and metal ion co-ordination might influence, or be influenced by, signal transduction cascades.

2.