Calcium Causes a Conformational Change in Lamin A Tail Domain that Promotes Farnesyl-Mediated Membrane Association
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Buehler_Calcium causes.pdf
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Author(s)
Kalinowski, Agnieszka
Qin, Zhao
Coffey, Kelli
Kodali, Ravi
Buehler, Markus J.
Dahl, Kris Noel
Losche, Mathias
Date Issued
May 2013
Journal
Biophysical Journal
Publisher
Elsevier
Citation
Kalinowski, Agnieszka, Zhao Qin, Kelli Coffey, Ravi Kodali, Markus J. Buehler, Mathias Losche, and Kris Noel Dahl. “Calcium Causes a Conformational Change in Lamin A Tail Domain That Promotes Farnesyl-Mediated Membrane Association.” Biophysical Journal 104, no. 10 (May 2013): 2246–2253. © 2013 Biophysical Society
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Final published version
Abstract
Lamin proteins contribute to nuclear structure and function, primarily at the inner nuclear membrane. The posttranslational processing pathway of lamin A includes farnesylation of the C-terminus, likely to increase membrane association, and subsequent proteolytic cleavage of the C-terminus. Hutchinson Gilford progeria syndrome is a premature aging disorder wherein a mutant version of lamin A, Δ50 lamin A, retains its farnesylation. We report here that membrane association of farnesylated Δ50 lamin A tail domains requires calcium. Experimental evidence and molecular dynamics simulations collectively suggest that the farnesyl group is sequestered within a hydrophobic region in the tail domain in the absence of calcium. Calcium binds to the tail domain with an affinity K[subscript D] ≈ 250 μM where it alters the structure of the Ig-fold and increases the solvent accessibility of the C-terminus. In 2 mM CaCl[subscript 2], the affinity of the farnesylated protein to a synthetic membrane is K[subscript D] ≈ 2 μM, as measured with surface plasmon resonance, but showed a combination of aggregation and binding. Membrane binding in the absence of calcium could not be detected. We suggest that a conformational change induced in Δ50 lamin A with divalent cations plays a regulatory role in the posttranslational processing of lamin A, which may be important in disease pathogenesis.
MIT Department
Massachusetts Institute of Technology. Department of Civil and Environmental Engineering
Massachusetts Institute of Technology. School of Engineering
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DOI of Published Version
https://doi.org/10.1016/j.bpj.2013.04.016
