Interfacial binding and aggregation of lamin A tail domains associated with Hutchinson-Gilford progeria syndrome
| Autor: | Siddharth Shenoy, Zhao Qin, Markus J. Buehler, Agnieszka Kalinowski, Peter N. Yaron, Mathias Lösche, Kris Noel Dahl |
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| Přispěvatelé: | Massachusetts Institute of Technology. Department of Civil and Environmental Engineering, Buehler, Markus J, Loesche, Mathias |
| Rok vydání: | 2014 |
| Předmět: |
Premature aging
Light Phosphorylcholine Lipid Bilayers Biophysics Plasma protein binding Phosphatidylserines Molecular Dynamics Simulation Biochemistry Article Progeria Prenylation medicine Inner membrane Humans Scattering Radiation Magnesium Lipid bilayer Ions Chemistry Organic Chemistry Osmolar Concentration Surface Plasmon Resonance medicine.disease Lamin Type A Protein Structure Tertiary Membrane Calcium Lamin Protein Binding |
| Zdroj: | PMC |
| ISSN: | 1873-4200 |
| Popis: | Hutchinson–Gilford progeria syndrome is a premature aging disorder associated with the expression of ∆50 lamin A (∆50LA), a mutant form of the nuclear structural protein lamin A (LA). ∆50LA is missing 50 amino acids from the tail domain and retains a C-terminal farnesyl group that is cleaved from the wild-type LA. Many of the cellular pathologies of HGPS are thought to be a consequence of protein–membrane association mediated by the retained farnesyl group. To better characterize the protein–membrane interface, we quantified binding of purified recombinant ∆50LA tail domain (∆50LA-TD) to tethered bilayer membranes composed of phosphatidylserine and phosphocholine using surface plasmon resonance. Farnesylated ∆50LA-TD binds to the membrane interface only in the presence of Ca[superscript 2 +] or Mg[superscript 2 +] at physiological ionic strength. At extremely low ionic strength, both the farnesylated and non-farnesylated forms of ∆50LA-TD bind to the membrane surface in amounts that exceed those expected for a densely packed protein monolayer. Interestingly, the wild-type LA-TD with no farnesylation also associates with membranes at low ionic strength but forms only a single layer. We suggest that electrostatic interactions are mediated by charge clusters with a net positive charge that we calculate on the surface of the LA-TDs. These studies suggest that the accumulation of ∆50LA at the inner nuclear membrane observed in cells is due to a combination of aggregation and membrane association rather than simple membrane binding; electrostatics plays an important role in mediating this association. National Institute of General Medical Sciences (U.S.) (1R01-GM101647) United States. Office of Naval Research. Presidential Early Career Award for Scientists and Engineers (N000141010562) National Institutes of Health (U.S.) (U01 EB014976) |
| Databáze: | OpenAIRE |
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