Kris N. Dahl

CMU Depts. of Biomed. Eng. and Chem. Eng.

412-268-9609, krisdahl@cmu.edu

The structural proteins of the nucleus primarily reside at the nuclear envelope and are responsible for maintaining mechanical integrity. Nuclear intermediate filaments of lamin A and lamin B form the nuclear lamina network stabilized by associated proteins. Both mechanical stability and mechano-sensitive gene expression are altered in cells with mutations in lamin proteins, including Hutchison-Gilford progeria syndrome (HGPS). In HGPS, a mutant form of lamin A called progerin results from the activation of a cryptic splice site. Progerin is truncated by fifty amino acids and retains a terminal farnesylation normally cleaved in wild-type lamin A. In cells, progerin accumulates at the nuclear membrane resulting in structural and mechanical anomalies of the nucleus. We use purified protein fragments of lamin A and progerin to quantify changes in molecular stability and quantify protein-membrane binding in vitro.