Student Theses and Dissertations

Date of Award

1987

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Abstract

Lamins A, Band C are the major polypeptides of the nuclear lamina, the filamentous meshwork intercalated between chromatin and the inner nuclear membrane. Amino acid sequences have been deduced from cDNA clones of human lamins A and C which show identity with the exception of an additional 98 amino acid residue carboxyl-terminal tail present only in lamin A and a 6 amino acid residue stretch at the carboxyl terminus of lamin C. The lamin A precursor has a predicted MW of 74 kDa while lamin C has a predicted MW of 65 kDa. The lamins have several structural features that identify them as members of the family of intermediate filament proteins. Both lamins share an approximately 360 amino acid residue domain of α-helical conformation that, in turn, shows primary and secondary structural homology with the a-helical rod domain of the intermediate filament proteins. However, the lamin α-helical domain is 14% larger than that of the intermediate filament proteins. Analogous to the intermediate filament protein α-helical domain, the lamin a-helical domain contains three regions (lA, lB and 2) of heptad repeats where the first and fourth residue of each heptad is usually hydrophobic or nonpolar. This results in an apolar stripe down one side of the α-helix. Lamins A and C may therefore assemble into coiled coil homodimers by interactions of their α-helical domain. Coi11B of the lamins is approximately twice the size of Coil 1 B of intermediate filament proteins, thus accounting for the larger size of the lamin α-helical domain. The highly conserved sequences found at the amino and carboxyl ends of the a-helical domains of all classes of intermediate filament proteins, as well as the highly conserved positions of the intercoillinkers, are present in the lamins as well. The lamins share an extra-helical 30 amino acid residue amino-terminal domain that bears no homology to any known intermediate filament protein sequence, yet has a slightly basic character (Arg residues) analogous to nonepithelial intermediate filament proteins. The extra-helical carboxyl-terminal domain shared by both lamins contains a putative nuclear localization signal and an abundance of Ser residues. These Ser residues may be involved in the phosphorylation and dephosphorylation events that coincide with lamina disassembly and reassembly, respectively, during mitosis. The unique lamin A carboxyl-terminal tail is high in Gly and Ser residues and shows limited homology to head and tail regions of Type I and Type II keratins. Thus, nuclear lamins may initiate assembly into a filamentous lamina by interactions based on properties found among all classes of intermediate filament proteins.

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