The Department of Biomedicine

BBB seminar: Emanuel E. Strehler

Human calmodulin: Why multiple genes for an identical protein?

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Emanuel E. Strehler
Program in Molecular Neuroscience, Mayo Graduate School and Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA

Calmodulin (CaM) is a ubiquitous protein in eukaryotes where it acts as a principal transducer of the Ca2+ signal [1]. In humans and other mammals, CaM is encoded by three separate genes located on different chromosomes. These genes are remarkable because they specify an identical protein although their nucleotide coding sequences differ maximally due to variable codon usage [2]. Why have multiple CaM genes with an identical protein-coding potential been conserved through evolution? True genetic redundancy is unlikely because the absence of strong selective pressure on the "backup" genes should lead to the accumulation of mutations in the "extra" genes. Rather, we speculate that the different genes fulfill specific roles in providing optimal levels of CaM during development, in different tissues, and in different intracellular compartments [3]. At the mRNA level, the products of the three CaM genes are unique and individually identifiable. Could the key to understanding the evolutionary maintenance of multiple CaM genes lie in information stored in the nucleotide sequence and/or the tertiary structure of each CaM mRNA? We determined CaM transcript regulation in differentiating human IMR-32 neuroblastoma cells and found that while all three genes were expressed, the 4.1 kb CALM1 mRNA was specifically upregulated about two-fold during differentiation [4]. This increase in the "long" CaLM1 mRNA correlated with neurite extension and was largely due to specific transcript stabilization. However, the total level of CaM did not change significantly throughout differentiation. In situ hybridization using fluorescently labeled nucleotides showed the 4.1 kb CALM1 transcript to be present in the cell body but intriguingly, also in extending neurites. This suggests that specific CaM transcripts are actively transported to the growing dendrites where they may become part of a pool of stored mRNAs available for the regulated and local synthesis of CaM. We propose a model whereby unique post-transcriptional and translational mechanisms, combined with differential gene regulation provide a rationale for the evolutionary maintenance of multiple genes for an identical calmodulin protein.

Literature cited:
[1] Klee CB and Vanaman TC. Adv Prot Chem 35:213-321 (1982).
[2] Fischer R, et al. J Biol Chem 263:17055-17062 (1988).
[3] Toutenhoofd SL and Strehler EE. Cell Calcium 28:83-96 (2000).
[4] Toutenhoofd SL and Strehler EE. Biochim Biophys Acta 1600:95-104 (2002).

Emanuel E. Strehler

Prof. Strehler's main current research relates to the important role of Ca2+ signaling in the control of eukaryotic cell function. Thus, some of his research focuses on the biochemical, molecular, and cellular basis for localized Ca2+ signaling and transmembrane Ca2+ transport, and the role that these processes play in normal and pathological cell function. One main topic of his research is to better understand the regulation and physiological role of the plasma membrane Ca2+ pumps. Another major topic is concerned with an intriguing epithelial-specific and tumor-sensitive Ca2+ binding protein named calmodulin-like protein (CLP). Of particular interest are recent data suggesting that CLP interacts with a novel unconventional myosin (myosin-10) that appears to be important for filopodial cell motility. Finally, Prof. Strehler and his group are interested in the significance of the highly conserved calmodulin multigene family, and specifically in its role in providing subcellular control of calmodulin availability. They have recently presented data showing that different calmodulin mRNA transcripts are localized differentially in human neuroblastoma cells indicating that individual, specific calmodulin transcripts may have different roles in neuronal functions.

Homepage: http://mayoresearch.mayo.edu/mayo/research/staff/strehler_ee.cfm