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Binding of Prion Proteins to Lipid Membranesq BBRC Biochemical and Biophysical Research Communications 313 (2004) 559–567 www.elsevier.com/locate/ybbrc Binding of prion proteins to lipid membranesq Peter Critchley, Jurate Kazlauskaite, Robert Eason, and Teresa J.T. Pinheiro* Department of Biological Sciences, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK Received 10 November 2003 Abstract A key molecular event in prion diseases is the conversion of the normal cellular form of the prion protein (PrPC) to an aberrant form known as the scrapie isoform, PrPSc. Under normal physiological conditions PrPC is attached to the outer leaflet of the plasma membrane via a GPI-anchor. It has been proposed that a direct interaction between PrP and lipid membranes could be involved in the conversion of PrPC to its disease-associated corrupted conformation, PrPSc. Recombinant PrP can be refolded into an a-helical structure, designated a-PrP isoform, or into b-sheet-rich states, designated b-PrP isoform. The current study investigates the binding of recombinant PrP isoforms to model lipid membranes using surface plasmon resonance spectroscopy. The binding of a- and b-PrP to negatively charged lipid membranes of POPG, zwitterionic membranes of DPPC, and model raft membranes composed of DPPC, cholesterol, and sphingomyelin is compared at pH 7 and 5, to simulate the environment at the plasma membrane and within en- dosomes, respectively. It is found that PrP binds strongly to lipid membranes. The strength of the association of PrP with lipid membranes depends on the protein conformation and pH, and involves both hydrophobic and electrostatic lipid–protein interac- tions. Competition binding measurements established that the binding of a-PrP to lipid membranes follows a decreasing order of affinity to POPG > DPPC > rafts. Ó 2003 Elsevier Inc. All rights reserved. Keywords: Prion protein; Raft membranes; SPR Transmissible spongiform encephalopathies (TSEs), erties. PrPC is rich in a-helical structure, monomeric, also known as prion diseases, are associated with the and susceptible to enzyme digestion, whereas PrPSc has a conversion of the benign cellular form of the prion large content of b-sheet, forms highly insoluble aggre- protein (PrPC) into an infectious scrapie isoform (PrPSc) gates, and is partially resistant to proteolytic digestion [1]. The transition between the cellular form and PrPSc [2,3]. It is apparent that a major refolding event under- occurs by an unidentified post-translational mechanism lying the conversion of PrPC to PrPSc plays a key role in and appears to take place without any detectable co- the pathogenesis of prion diseases [4]. However, the valent modifications to the protein molecule. A large molecular details of this conformational transition are body of experimental evidence indicates that the fun- not clearly understood. damental difference between the two forms of PrP re- The prion is a N-glycosylated protein, which occurs sides in their conformation, which results in predominantly in neurons where it is anchored to the considerable differences in their physicochemical prop- plasma membrane via a glycosyl phosphatidylinositol (GPI) anchor [5]. Several experimental observations [6– 9] suggest that an interaction of PrP with the mem- q Abbreviations: CD, circular dichroism; chol, cholesterol; DPPC, dipalmitoylphosphatidylcholine (1,2-dipalmitoyl-sn-glycero-3-phos- brane surface may play a role in the conversion of C Sc C phocholine); EM, electron microscopy; lyso-PC, monoacyl-glycero- PrP to PrP . In particular, the fact that PrP is re- phosphocholine; lyso-PS, monoacyl-glycerophosphoserine; MOG, leased from the cell surface after digestion with phos- monooleoylglycerol; PrP, prion protein; POPG, palmitoyloleoylphos- phatidylinositol-specific phospholipase C (PIPLC) and phatidylglycerol (1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-rac-(1- PrPSc is not after similar treatment [7,8] strongly sup- glycerol)); SHaPrP, Syrian hamster prion protein; SM, sphingomyelin; SPR, surface plasmon resonance. ports the idea that an altered membrane association of * Corresponding author. Fax: +44-24-7652-3701. PrP may be an important factor in the mechanism of E-mail address: [email protected] (T.J.T. Pinheiro). prion diseases. 0006-291X/$ - see front matter Ó 2003 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2003.12.004 560 P. Critchley et al. / Biochemical and Biophysical Research Communications 313 (2004) 559–567 Like other GPI-anchored proteins, PrPC is segregated Recombinant PrP can be refolded as a predominantly into cholesterol and sphingomyelin-rich domains or li- a-helical conformation, designated a-PrP, or forms rich pid rafts in the plasma membrane [10–12] from where its in b-sheet structure, designated b-PrP isoforms. metabolic fate is determined. From the plasma mem- Whereas a-PrP is monomeric and susceptible to enzyme brane PrPC can be recycled, degraded or possibly con- digestion, b-PrP isoforms are oligomeric, partially re- verted to PrPSc. The subcellular site for the formation of sistant to proteolytic digestion, and form insoluble ag- PrPSc is unknown; however, conversion occurs after gregates and fibrils [28]. Thus, recombinant b-sheet PrPC reaches the plasma membrane [13,14]. A recent forms of PrP have properties of intermediate confor- study of PrP conversion in a cell-free system utilising mations of PrP that lead to PrPSc. In previous studies we purified raft membranes showed that conversion of raft- have characterised the interaction of a- and b-isoforms associated GPI-anchored PrPC to PrPSc requires inser- of the truncated protein PrP(90–231) to model lipid tion of PrPSc into the lipid membrane [15]. Evidence membranes, both at pH 7 and 5, to model the pH from scrapie-infected cultured cells implicates the plas- environment of the plasma membrane and within en- ma membrane and endocytic organelles as relevant sites, dosomes, respectively [29,30]. These studies showed that but it is unclear which provides a more favourable en- a- and b-PrP have different binding affinities to lipid vironment for conversion and whether compartments membranes and exhibit a different pH-dependent bind- along the secretory pathway might also be involved. ing behaviour. The key findings, resulting from a com- Once PrPSc is formed, it appears to accumulate in late bination of fluorescence, CD, FTIR, and EM studies, endosomes, lysosomes, and on the cell surface [12,16,17] were that: (a) binding of a- and b-PrP to negatively or in extracellular spaces in the form of amorphous charged lipid membranes results in increased b-sheet deposits, diffuse fibrils or dense amyloid plaques [18]. structure in PrP, which destabilises the lipid membrane In addition to fully secreted GPI-anchored PrP, an- and leads to amorphous aggregates of PrP; (b) binding chorless forms of PrP have been shown to be produced of a-PrP to raft membranes increases a-helical structure, in the ER or released as soluble forms. Two trans- which does not destabilise the lipid membrane and does membrane forms of PrP, either with the amino- or not lead to PrP aggregation; and (c) binding of b-PrP to carboxy-terminus in the lumen, are associated with the rafts partially unfolds PrP, which does not destabilise ER membrane via a common transmembrane segment the lipid membrane but leads to fibrillisation of PrP. comprising residues 113–135 [19,20]. Release of soluble In the current study we investigate the binding of forms of PrP (lacking GPI anchor) from cells was first a-PrP to lipid membranes using surface plasmon res- reported some years ago [21–24]. More recently, similar onance (SPR). Binding measurements were carried at results have been obtained using splenocytes or cere- pH 7 to represent the pH surrounding the plasma bellar granule neurons from transgenic mice overex- membrane, and at pH 5 to model the acidic environ- pressing PrP [25]. Also, it has been reported that 10–20% ment of endocytic vesicles. The binding of PrP to of PrPSc molecules extracted from infected hamsters are membranes was studied with model lipid membranes truncated at Gly228 and therefore lacking GPI anchor composed of a single lipid or a mixture of lipids. Single [26]. lipid vesicles composed of negatively charged lipid, The majority of PrPSc generated in infected animals palmitoyloleoylphosphatidylglycerol (POPG), or zwit- contains a GPI anchor and the relevance of anchorless terionic lipid, dipalmitoylphosphatidylcholine (DPPC), forms of PrP is not clear. However, it is possible that were employed to identify the electrostatic and hydro- anchorless forms of PrP may be physiologically relevant phobic modes of interaction of PrP to lipid mem- in the conversion process of PrP. A recent study has branes. Mixed membranes composed of DPPC, tested the effect of GPI anchor on prion conversion [27]. cholesterol, and sphingomyelin (SM) were used to This work shows that either GPI-anchored (GPIþ) PrP model the composition of rafts, where PrP accumulates or an anchor-deficient (GPIÀ) form of PrP expressed in in the plasma membrane. fibroblasts is stably associated with rafts, and the latter alternative mode of membrane association (independent of GPI) was not detectably altered by glycosylation and Materials and methods was not markedly reduced by deletion of the N-termi- nus. Furthermore, using a cell-free conversion assay, it Materials. Cholesterol, POPG, and sphingomyelin were purchased þ Sc was found that GPI PrP was not converted to PrP from Avanti Polar Lipids (Alabaster, AL). DPPC and MOG were without the action of PIPLC or addition of the mem- from Sigma–Aldrich (Dorset, UK). brane-fusion agent polyethylene glycol (PEG), whereas Expression, purification, and refolding of PrP. Syrian hamster re- GPIÀ PrP was converted without PIPLC or PEG combinant prion protein SHaPrP(90–231) was expressed using an al- kaline phosphatase promoter in a protease-deficient strain of treatment. These findings support the view that addi- Escherichia coli (27C7) [31] and purified as described previously tional direct lipid–polypeptide interactions may play a [29,30]. PrP was refolded into an a-helical conformation (a-PrP) or to a role in the conversion of PrPC to PrPSc.
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