Enthalpy-Driven Apolipoprotein A-I and Lipid Bilayer Interaction Indicating Protein Penetration upon Lipid Binding

Arnulphi, Cristina; Jin, Lihua; Tricerri, and M. Alejandra; Jonas, Ana

doi:10.1021/bi036118k

Cited by 43 publications

(63 citation statements)

References 23 publications

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“…Consequently, lipid-bound α-helices can facilitate binding and insertion of additional helices. The positive cooperativity in the binding and insertion of amphipathic α-helices into the lipid surface, which was also suggested in other apolipoprotein studies (19), may result from lipid-mediated interactions (bound α-helices perturb adjacent lipid molecules thereby helping to accommodate additional helices) and, possibly, from direct protein-protein interactions (lipid-bound α-helices may provide a template for folding and insertion of additional helices).…”

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

confidence: 59%

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 Isupporting

confidence: 59%

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

2007

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“…The R173S apoA-I variant displayed a small but significant decrease in enthalpy compared with WT apoA-I, whereas the R173K mutation had no effect on the binding enthalpy. The exothermic enthalpy of binding is the major component of the favorable free energy of binding of apoA-I to SUV, and the increase in a-helix content associated with such binding is largely responsible for this enthalpy (29,51). Thus, the reductions in enthalpy compared with WT apoA-I shown in Table 3 are a consequence of a smaller increase in a-helix content upon lipid interaction.…”

Section: Interactions Of Apoa-i Variants With Lipidmentioning

confidence: 99%

Structural and functional consequences of the Milano mutation (R173C) in human apolipoprotein A-I

Alexander

Tanaka

Kono

et al. 2009

Journal of Lipid Research

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Carriers of the apolipoprotein A-I Milano (apoA-I M ) variant, R173C, have reduced levels of plasma HDL but no increase in cardiovascular disease. Despite intensive study, it is not clear whether the removal of the arginine or the introduction of the cysteine is responsible for this altered functionality. We investigated this question using two engineered variations of the apoA-I M mutation: R173S apoA-I, similar to apoA-I M but incapable of forming a disulfide bond, and R173K apoA-I, a conservative mutation. Characterization of the lipid-free proteins showed that the order of stability was wild type≈R173K.R173S.R173C. Compared with wildtype apoA-I, apoA-I M had a lower affinity for lipids, while R173S apoA-I displayed intermediate affinity. The in vivo effects of the apoA-I variants were measured by injecting apoA-I-expressing adeno-associated virus into apoA-I-null mice. Mice that expressed the R173S variant again showed an intermediate phenotype. Thus, both the loss of the arginine and its replacement by a cysteine contribute to the altered properties of apoA-I M . The arginine is potentially involved in an intrahelical salt bridge with E169 that is disrupted by the loss of the positively charged arginine and repelled by the cysteine, destabilizing the helix bundle domain in the apoA-I molecule and modifying its lipid binding

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“…As listed in Table 1, the obtained parameters indicate that the 1-83 variants bind to SUV with high affinity similarly to full-length apoA-I (37), and the G26R mutation reduces the binding capacity. In addition, binding of the 1-83 variants to the SUV surface is an enthalpically favorable but entropically unfavorable process (37,48).…”

Section: Effects Of Membrane Binding On Fibril Formation Of Apoa-i 1-83mentioning

confidence: 99%

Amyloidogenic Mutation Promotes Fibril Formation of the N-terminal Apolipoprotein A-I on Lipid Membranes

Mizuguchi

Ogata

Mikawa

et al. 2015

Journal of Biological Chemistry

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Background:The N-terminal fragment of amyloidogenic apoA-I mutants deposits as fibrils by unknown mechanisms. Results: The G26R mutation partially prevents helix formation of the N-terminal fragment upon lipid binding, thereby facilitating ␤-transition and fibril formation. Conclusion: Membrane binding modulates fibril formation of apoA-I through partially destabilized helical conformation. Significance: The results reveal a new pathway for amyloid fibril formation by apoA-I.

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Enthalpy-Driven Apolipoprotein A-I and Lipid Bilayer Interaction Indicating Protein Penetration upon Lipid Binding

Cited by 43 publications

References 23 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

Structural and functional consequences of the Milano mutation (R173C) in human apolipoprotein A-I

Amyloidogenic Mutation Promotes Fibril Formation of the N-terminal Apolipoprotein A-I on Lipid Membranes

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