Interfacial binding and aggregation of lamin A tail domains associated with Hutchinson–Gilford progeria syndrome
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Buehler_interfacial binding.pdf
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Author(s)
Kalinowski, Agnieszka
Yaron, Peter N.
Qin, Zhao
Shenoy, Siddharth
Dahl, Kris Noel
Buehler, Markus J
Loesche, Mathias
Date Issued
August 2014
Journal
Biophysical Chemistry
Publisher
Elsevier
Citation
Kalinowski, Agnieszka et al. “Interfacial Binding and Aggregation of Lamin A Tail Domains Associated with Hutchinson–Gilford Progeria Syndrome.” Biophysical Chemistry 195 (2014): 43–48.
Version
Author's final manuscript
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Department of Civil and Environmental Engineering
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DOI of Published Version
https://doi.org/10.1016/j.bpc.2014.08.005
