The 11‐mer repeats of human α‐synuclein in vesicle interactions and lipid composition discrimination: A cooperative role

Bisaglia, Marco; Schievano, Elisabetta; Caporale, Andrea; Peggion, Evaristo; Mammi, Stefano

doi:10.1002/bip.20440

Cited by 36 publications

(34 citation statements)

References 32 publications

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“…This intramolecular cooperativity is a result of apolipoprotein evolution from the apoC-I-related precursor via the duplication and deletion of the 11-mer codon repeats (51). Interestingly, similar 11-mer helical repeats in α-syniclein show cooperative binding to phospholipid surface (52). Thus, the cooperative binding of α-helices to phospholipid surface reported here is not limited to apolipoproteins but may extend to functional reactions in other lipid surface-binding proteins and peptides.…”

Section: Bound α-Helices Facilitate Insertion Of Additional Helices Imentioning

confidence: 66%

Role of Secondary Structure in Protein−Phospholipid Surface Interactions: Reconstitution and Denaturation of Apolipoprotein C-I:DMPC Complexes

2007

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Protein binding to phospholipid surface is commonly mediated by amphipathic α-helices. To understand the role of α-helical structure in protein-lipid interactions, we used discoidal lipoproteins reconstituted from dimyristoyl phosphatidylcholine (DMPC) and human apolipoprotein C-I (apoC-I, 6 kD) or its mutants containing single Pro substitutions along the sequence and differing in their α-helical content in solution (0-48%) and on DMPC (40-75%). Thermal denaturation revealed that lipoprotein stability correlates weakly with the protein helix content: proteins with higher α-helical content on DMPC may form more stable complexes. Lipoprotein reconstitution upon cooling from the heat-denatured state and DMPC clearance studies revealed that protein secondary structure in solution and on DMPC correlates strongly with the maximal temperature of lipoprotein reconstitution: more helical proteins can reconstitute lipoproteins at higher temperatures. Interestingly, at T c =24 °C of the DMPC gel-to-liquid crystal transition, the clearance rate is independent of the protein helical content. Consequently, if the packing defects at the phospholipid surface are readily available (e.g. at the lipid phase boundary), protein insertion into these defects is independent of the secondary structure in solution. However, if hydrophobic defects are limited, protein binding and insertion is aided by other surface-bound proteins and depends on their helical propensity: the larger the propensity the faster the binding and the broader its temperature range. This positive cooperativity in α-helical binding to phospholipid surface, which may result from direct and/or lipid-mediated protein-protein interactions, may be important for lipoprotein metabolism and for protein-membrane binding. KeywordsHigh-density lipoprotein; kinetic stability; lipid fusion; vesicle clearance; atherosclerosis Protein binding to phospholipid surface is an important step in many biological reactions including apolipoprotein exchange among plasma lipoproteins, activation of lipid-regulated enzymes such as phosphoglycerate kinase (PGK) or CTP:phosphocholine cytidylyltransferase (CCT), synuclein aggregation in Parkinson's disease, lipid storage in adypocytes, and binding of antimicrobial peptides to cell surfaces. The binding depends on the structural and physicochemical properties of both proteins and lipids and is facilitated by the hydrophobic defects on the lipid surface that form primary protein binding sites (1-4). The common lipid surface-binding motif found in many proteins, including apolipoproteins, perilipin, synucleins, CTT and PGK, is amphipathic α-helix comprised of 11-mer sequence repeats ((5,6) and references therein). The extended apolar face of such a helix is optimized for interactions with Corresponding author: Dr. Olga Gursky, Department of Physiology and Biophysics, W329, Boston University School of Medicine, 715 Albany Street, Boston MA 02118, E-mail: gursky@bu.edu, Phone: (617) FAX: (617) NIH-PA Author ManuscriptNIH-PA Author Manuscri...

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Section: Bound α-Helices Facilitate Insertion Of Additional Helices Imentioning

confidence: 66%

Role of Secondary Structure in Protein−Phospholipid Surface Interactions: Reconstitution and Denaturation of Apolipoprotein C-I:DMPC Complexes

2007

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“…[10,13,33,34] It suggests that, at lower charge density, the binding affinity of helix 1 is stronger than that of helix 2. This implies that the binding of aS to membranes could be initiated in the N-terminal part of aS and that subtle alterations in the membrane composition could provide a means to manipulate further binding events along the polypeptide.…”

Section: Discussionmentioning

confidence: 95%

Spin‐Label EPR on α‐Synuclein Reveals Differences in the Membrane Binding Affinity of the Two Antiparallel Helices

et al. 2008

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The putative function of the Parkinson's disease-related protein alpha-Synuclein (alphaS) is thought to involve membrane binding. Therefore, the interaction of alphaS with membranes composed of zwitterionic (POPC) and anionic (POPG) lipids was investigated through the mobility of spin labels attached to the protein. Differently labelled variants of alphaS were produced, containing a spin label at positions 9, 18 (both helix 1), 69, 90 (both helix 2), and 140 (C terminus). Protein binding to POPC/POPG vesicles for all but alphaS140 resulted in two mobility components with correlation times of 0.5 and 3 ns, for POPG mole fractions >0.4. Monitoring these components as a function of the POPG mole fraction revealed that at low negative-charge densities helix 1 is more tightly bound than helix 2; this indicates a partially bound form of alphaS. Thus, the interaction of alphaS with membranes of low charge densities might be initiated at helix 1. The local binding information thus obtained gives a more differentiated picture of the affinity of alphaS to membranes. These findings contribute to our understanding of the details and structural consequences of alphaS-membrane interactions.

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“…Such a periodicity is characteristic of the amphipathic lipid-binding α-helical domains of apolipoproteins [122,123], which have been extensively studied and assigned to subclasses according to their unique structural and functional properties [125,126]. These seven imperfect 11-residue repeat sequences were predicted to form five amphipathic helices on the aminoterminal half of human α-synuclein [127][128][129], with helices 1-4 predicted to associate with lipid vesicles [130,131], whereas helix 5 being likely responsible for protein-protein interactions [128]. It has been pointed out that α-synuclein shares the defining properties of the class A2 lipid-binding helix, distinguished by clustered basic residues at the polar-apolar interface, positioned ±100° from the center of apolar face; predominance of lysines relative to arginines among these basic residues; and several glutamate residues at the polar surface [125,126,131].…”

Section: Conformational Behavior Of α-Synuclein: a Protein-chameleon mentioning

confidence: 99%

Amyloidogenesis of Natively Unfolded Proteins

Uversky

2008

CAR

174

152

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Aggregation and subsequent development of protein deposition diseases originate from conformational changes in corresponding amyloidogenic proteins. The accumulated data support the model where protein fibrillogenesis proceeds via the formation of a relatively unfolded amyloidogenic conformation, which shares many structural properties with the pre-molten globule state, a partially folded intermediate first found during the equilibrium and kinetic (un)folding studies of several globular proteins and later described as one of the structural forms of natively unfolded proteins. The flexibility of this structural form is essential for the conformational rearrangements driving the formation of the core cross-beta structure of the amyloid fibril. Obviously, molecular mechanisms describing amyloidogenesis of ordered and natively unfolded proteins are different. For ordered protein to fibrillate, its unique and rigid structure has to be destabilized and partially unfolded. On the other hand, fibrillogenesis of a natively unfolded protein involves the formation of partially folded conformation; i.e., partial folding rather than unfolding. In this review recent findings are surveyed to illustrate some unique features of the natively unfolded proteins amyloidogenesis.

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The 11‐mer repeats of human α‐synuclein in vesicle interactions and lipid composition discrimination: A cooperative role

Cited by 36 publications

References 32 publications

Role of Secondary Structure in Protein−Phospholipid Surface Interactions: Reconstitution and Denaturation of Apolipoprotein C-I:DMPC Complexes

Role of Secondary Structure in Protein−Phospholipid Surface Interactions: Reconstitution and Denaturation of Apolipoprotein C-I:DMPC Complexes

Spin‐Label EPR on α‐Synuclein Reveals Differences in the Membrane Binding Affinity of the Two Antiparallel Helices

Amyloidogenesis of Natively Unfolded Proteins

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