Cell Signaling

Edited by Thomas W. Durso K.L. Schmeichel, M.C. Beckerle, "The LIM domain is a modular protein-binding interface," Cell, 79:211-9, 1994. (Cited in nearly 50 publications through August 1996) Comments by Mary C. Beckerle, University of Utah, Salt Lake City Its presence in several proteins that "play fundamental roles in development" is what led Karen L. Schmeichel and Mary C. Beckerle of the University of Utah, Salt Lake City, to begin studying the LIM domain, a zinc-binding protein sequence. LIFE AND LIM: From left, coauthors Mary C. Beckerle and Karen L. Schmeichel investigated a protein domain with major developmental functions. The LIM motif was first identified in three developmentally important transcription factors, Caenorhabditis elegans Lin-11, rat Isl-1, and C. elegans Mec-3, from which the acronym LIM is derived (G. Freyd et al., Nature, 344:876-9, 1990; O. Karlsson et al., Nature, 344:879-82, 1990). The functions of LIM proteins include signal transduction, transcriptional regulation, and cell-fate specification, explains Beckerle, a professor of biology at Utah. Some LIM proteins are found in cell nuclei, while others are concentrated at sites of cell adhesion to extracellular matrix. Beckerle and Schmeichel, who recently received her doctorate and is interviewing for postdoc positions, discovered that "LIM domains have a capacity to bind protein targets with high specificity." By determining that the LIM domain functions as a specific protein-binding interface, Beckerle notes, researchers can investigate how those "biologically significant" proteins work in living organisms. "The idea is that proteins that have LIM domains will be able to recruit specific protein partners and perhaps facilitate the assembly of macromolecular signaling complexes," she says. "It's clear from the physiological functions of many LIM domain proteins that they affect important cell behaviors. Ultimately, understanding that LIM domains specify the nature of protein binding partners may enable people to design specific inhibitors of those interactions, which may allow us to control LIM-dependent processes." Beckerle notes that until this paper, the function of the LIM domain had been the subject of considerable speculation among researchers. Some had maintained, for example, that it may interact directly with nucleic acids, such as DNA and RNA, and not with proteins. Schmeichel and Beckerle are now examining the possibility that the LIM domain can interact with both proteins and nucleic acids. "The ligand-binding specificity of the LIM domain is interesting to us because it is likely to have a big impact on the function of LIM proteins in cells," Beckerle states. "Many of them are transcription factors. Some are proto-oncogene products. Many play important roles in regulating differentiation during cell development." Beckerle attributes the paper's high citation rate to the fact that "LIM domains are present in so many biologically important molecules. . . . Because they're found in such a wide variety of proteins, people from a lot of diverse fields are interested in the structure and the function of the domain to learn more about the proteins they are studying." Since the publication of this paper, Beckerle and coworkers have been attempting to define further the structure and function of the LIM domain itself (G.C. Perez-Alvarado et al., Nature Structural Biology, 1:388-98, 1994; G.C. Perez-Alvarado et al., Journal of Molecular Biology, 257:153-74, 1996). In addition, they are examining zyxin and the cysteine-rich protein (CRP), a pair of cytoskeletal proteins whose binding played a key role in their studies on the LIM domain, to determine what effect they have on signaling from the cell surface to the cell interior. Other related studies include Schmeichel's research into the LIM domain's two zinc fingers "to see if either one is necessary and sufficient for the protein-binding specificity of the domain." They also are investigating Drosophila and mouse cells "to understand the physiological roles of the LIM proteins zyxin and CRP, especially their involvement in information processing and communication within the cell."

Cell Signaling

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