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Membrane-mediated peptide conformation change from alpha-monomers to beta-aggregates.

ABSTRACT: Jarrett and Lansbury's nucleation-dependent polymerization model describes the generic process of beta-amyloid formation for a large number of diverse proteins and peptides. Here, we discuss a case of membrane-mediated nucleation that leads to beta-aggregation. We studied the membrane-mediated conformation changes of the peptide penetratin, and the results of our study led us to a free-energy description for a membrane-mediated version of the Jarrett-Lansbury model. Like the prototype beta-amyloid peptide Alzheimer's Abeta 1-40, penetratin is a random-coil monomer in solution but changes to alpha-helical or beta-like conformations in the presence of anionic lipid membranes. We measured the correlations between the membrane-bound conformation of penetratin and its effect on the bilayer thickness in four different lipids with various degrees of chain unsaturation. We found a new lipid chain effect on peptide conformation. Our results showed that the interface of a lipid bilayer provided energetically favorable binding sites for penetratin in the alpha-helical form. However, increasing the bound molecules/lipid ratio elevated the energy level of the bound states toward a higher level that favored creation of small beta-aggregates. The binding to the beta-aggregate became more energetically favorable as the aggregate grew larger. The peptide aggregates were visible on the surface of giant unilamellar vesicles. Thus, membrane binding facilitates nucleation-dependent beta-aggregation, which could be the prototype for the general membrane-mediated pathway to beta-amyloid formation.

SUBMITTER: Lee CC

PROVIDER: S-EPMC2872214 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Membrane-mediated peptide conformation change from alpha-monomers to beta-aggregates.

Lee Chang-Chun CC Sun Yen Y Huang Huey W HW

Biophysical journal 20100501 10

Jarrett and Lansbury's nucleation-dependent polymerization model describes the generic process of beta-amyloid formation for a large number of diverse proteins and peptides. Here, we discuss a case of membrane-mediated nucleation that leads to beta-aggregation. We studied the membrane-mediated conformation changes of the peptide penetratin, and the results of our study led us to a free-energy description for a membrane-mediated version of the Jarrett-Lansbury model. Like the prototype beta-amylo ...[more]

PMID: 20483332

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Project description:Marburg virus (MARV) encodes a nucleoprotein (NP) to encapsidate its genome by oligomerization and form a ribonucleoprotein complex (RNP). According to previous investigation on nonsegmented negative-sense RNA viruses (nsNSV), the newly synthesized NPs must be prevented from indiscriminately binding to noncognate RNAs. During the viral RNA synthesis process, the RNPs undergo a transition from an RNA-bound form to a template-free form, to open access for the interaction between the viral polymerase and the RNA template. In filoviruses, this transition is regulated by VP35 peptide and other viral components. To further understand the dynamic process of filovirus RNP formation, we report here the structure of MARV NPcore, both in the apo form and in the VP35 peptide-chaperoned form. These structures reveal a typical bilobed structure, with a positive-charged RNA binding groove between two lobes. In the apo form, the MARV NP exists in an interesting hexameric state formed by the hydrophobic interaction within the long helix of the NPcore C-terminal region, which shows high structural flexibility among filoviruses and may imply critical function during RNP formation. Moreover, the VP35 peptide-chaperoned NPcore remains in a monomeric state and completely loses its affinity for single-stranded RNA (ssRNA). The structural comparison reveals that the RNA binding groove undergoes a transition from closed state to open state, chaperoned by VP35 peptide, thus preventing the interaction for viral RNA. Our investigation provides considerable structural insight into the filovirus RNP working mechanism and may support the development of antiviral therapies targeting the RNP formation of filovirus.IMPORTANCE Marburg virus is one of the most dangerous viruses, with high morbidity and mortality. A recent outbreak in Angola in 2005 caused the deaths of 272 persons. NP is one of the most essential proteins, as it encapsidates and protects the whole virus genome simultaneously with self-assembly oligomerization. Here we report the structures of MARV NPcore in two different forms. In the MARV NP apo form, we identify an interesting hexamer formed by hydrophobic interaction within a long helix, which is highly conserved and flexible among filoviruses and may indicate its critical function during the virus RNP formation. Moreover, the structural comparison with the NP-VP35 peptide complex reveals a structural transition chaperoned by VP35, in which the RNA binding groove undergoes a transition from closed state to open state. Finally, we discussed the high conservation and critical role of the VP35 binding pocket and its potential use for therapeutic development.

Dataset Information

Membrane-mediated peptide conformation change from alpha-monomers to beta-aggregates.

Publications

Membrane-mediated peptide conformation change from alpha-monomers to beta-aggregates.

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