cDNA sequencing of nuclear lamins A and C reveals primary and secondary structural homology to intermediate filament proteins.

Abstract

The amino acid sequences. deduced from cDNA clones of human lamin A and lamin C show identity between these two lamins except for an extra 9.0-kDa carboxylterminal tail that is present only in lamin A. Both latins A and C contain an a-helical domain of approximately 360 residues that shows striking homology to a corresponding a-helical rod domain that, is the structural hallmark of all intermediate filament proteins. How'ever, the lamin a-helical domain Implications of the presence of these and other domains in lamins A and C for the assembly of the nuclear lamina are discussed.The nuclear lamina is a polymeric structure that is intercalated between chromatin and the inner membrane of the nuclear envelope. In mammalian cells the lamina consists primarily ofthree proteins (1-4) that have been termed lamins A (70 kDa), B (67 kDa), and C (60 kDa) (5). Peptide maps of lamins A and C are similar, but they are different from those of lamin B (6). However, certain monoclonal antibodies have been shown to crossreact with all three lamins, indicating that some epitopes are shared by all three lamins (7,8).The lamins have been shown to be synthesized throughout the cell cycle (9). In vitro translation of mRNA (10) showed that lamins A and C are synthesized from separate mRNAs with lamin A being made as a precursor approximately 2 kDa larger than mature lamin A. The precursor is converted into mature lamin A only after incorporation into the lamina structure, as shown by pulse-chase experiments (9).The lamina is depolymerized during mitotic prophase by a process that may involve transient hyperphosphorylation (5).Concomitant with a gradual dephosphorylation, the lamins repolymerize in telophase (3,5). How the regular protein meshwork (2) that constitutes the lamina is assembled from the three lamins is not known. The lamins must contain domains that are involved in this polymerization and that interact with chromatin on the nucleoplasmic face of the lamina, with the inner nuclear membrane on the other face of the lamina, and, most likely, with nuclear pore complexes (1, 2). As such domains could be revealed from the amino acid sequences of the lamins, we decided to clone their cDNAs. We report here the deduced amino acid sequences for lamins A and C. While The publication costs of this article were defrayed in part by page charge payment., This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Activation of the lamin A gene during rat liver development

“…Immunocytochemical studies have revealed that m~differentiated mouse embryonal carcinoma cell lines and e~rly mouse embryos contain only lamin B, whereas lamins A and C are expressed later in embryogenesis, when tissue d~ fferentiation is initiated [5,6]. Lamins A and C have identical maino acid sequences except for their C-terminal domains, aid most probably arise by differential splicing of RNA from a single lamin A gene [3,9,10]. Although structure-functi, m correlations of the lamins have been examined in detail, there have been relatively few studies on the transcriptional status of the lamin genes [11,12].…”

Inner nuclear membrane and signal transduction

“…The pore membranes connect the inner and outer nuclear membranes at numerous points and are associated with nuclear pore complexes. The nuclear lamina is composed of intermediate filament proteins called lamins, which polymerize to form the filamentous lamina primarily localized at the inner surface of the inner nuclear membrane [Gerace et al, 1978;Aebi et al, 1986;Fisher et al, 1986;Goldman et al, 1986;McKeon et al, 1986]. While the lamins and lamina likely have several functions, one generally agreed upon is mechanical support for the nuclear envelope.…”

“…Several of these diseases result from mutations in A-type lamins. The major somatic cell A-type lamins are lamins A and C, which arise by alternative splicing or RNA encoded by the LMNA gene [Fisher et al, 1986;McKeon et al, 1986;Lin and Worman, 1993]. Lamins A and C are expressed in most terminally differentiated cells, making the fact that mutations in these proteins cause tissuespecific disorders somewhat surprising.…”

Structures of the lamin A/C R335W and E347K mutants: Implications for dilated cardiolaminopathies

“…According to their primary sequence, biochemical properties and expression patterns, lamins have been classified as A-and B-type, which are differentially expressed in cells. The Lamin AC gene (LMNA) maps on the long arm of chromosome 1 (1q21.2-q21.3) and encodes two main isoforms by alternative splicing [16], Lamin A and C, which are expressed exclusively in differentiated non-proliferating cells [2,10,12,13].…”