Nuclear Lamins and Laminopathies – Understanding the Complex Circuitry

by Prof. Kaushik Sengupta (Saha Institute of Nuclear Physics, Kolkata)

Tuesday, January 31, 2012 from 14:30 to 15:30 (Asia/Kolkata)
at Colaba Campus ( AG-66 )

TIFR, Colaba Mumbai 400005

Description

Lamins are architectural proteins of the nucleus and are poised to play important roles in diverse nuclear processes like replication, DNA damage repair, transcription. Lamins are among the most well characterized proteins studied hitherto in animal systems, yet the major question remains as to how exactly they modulate these nuclear processes. The Lamins belong to the type V intermediate filament protein family based on sequence homology classification. Mutations in the Lamin protein family especially the Lamin A/C cause several diseases affecting striated muscle, adipose tissue, peripheral nerve and also progeria phenotype. Dilated Cardiomyopathy (DCM) is classified as a striated muscle disorder which is characterized by ventricular dilation, hypertrophy, arrhythmic conduction defects and cardiac arrest. The meshwork of 10 nm filaments is the fundamental framework which performs functions like chromatin tethering to sequestering and positioning replication, transcription and DNA damage repair machineries. In this project we would focus on deciphering what are the structural changes associated with the point mutations of the Lamin A/C which are implicated in Dilated Cardiomyopathy. The mutations are predominantly in the central rod domain of the protein which forms the coiled coil dimer and this dimer is the first building block of higher order oligomerized structure of Lamins. In this project we are employing cell biology and biophysics to understand and delineate the roles of these mutations in causing DCM. We have initiated extensive morphological studies of wild type and mutant lamin transfected nuclei by confocal microscopy and electron microscopy. At the same time we have obtained preliminary results from rheological measurements which show different viscoelastic behavior of mutant lamins in comparison to the wild type.