( ver two decades ago but until recently...)Study shows how retinoic acid enters a cell's nucleus

Much like a doorway that requires a pass code to enter, CRABP-II can only move into a cell's nucleus if its amino acids are organized in a certain sequence, called a nuclear localization signal (NLS). However, CRABP-II does not have a recognizable NLS. Researchers have long wondered how proteins without an NLS enter a cell's nucleus.

By comparing the 3-D structures of the CRABP-II protein before and after it comes in contact with RA, Noy and Sessler made a startling discovery: When exposed to RA, three amino acids on the CRABP-II molecule flip their positions, exposing positive charges. Combined with the way the molecule is folded, this area suddenly looks like a classical NLS.

"This discovery creates a precedent for many other proteins that don't have an NLS, and it solves a mystery that has been in the literature for a long time," Noy says. "It explains a basic mechanism of how this protein, CRABP-II, gets into the nucleus, where it can act to suppress tumors."

CRABP-II is a member of a group of proteins called intracellular lipid binding proteins (ILBP), which don't have a recognizable NLS. But now researchers have something new to look for -- folds in a molecule's structure and amino acids that flip when exposed to a hormone or a drug. Noy currently is working with an ILBP that she has pinpointed as a pro-carcinogen -- it promotes cancer. Armed with new tools and knowledge, she hopes to figure out how to suppress the ability of this protein to move to the nucleus and promote cancer, perhaps by blocking the hormone that switches on its NLS.

In previous experiments with mice, Noy and her colleagues showed that by increasing CRABP-II levels within cells, tumor growth rates slow dramatically. The protein transfers RA rapidly and efficiently to the cell's nucleus. In this way, tumor growth may be inhibited using naturally occurring levels of RA, as oppo
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Source:Cornell University News Service