Calcium causes a conformational change in lamin A tail domain that promotes farnesyl-mediated membrane association

Agnieszka Kalinowski, Zhao Qin, Kelli Coffey, Ravi Kodali, Markus J. Buehler, Mathias Lösche, Kris Noel Dahl

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


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 KD ≈ 250 μM where it alters the structure of the Ig-fold and increases the solvent accessibility of the C-terminus. In 2 mM CaCl2, the affinity of the farnesylated protein to a synthetic membrane is KD ≈ 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.

Original languageEnglish (US)
Pages (from-to)2246-2253
Number of pages8
JournalBiophysical Journal
Issue number10
StatePublished - May 21 2013
Externally publishedYes

ASJC Scopus subject areas

  • Biophysics


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