Site for Proteolysis and Protein Interaction

Science's STKE  09 May 2006:
Vol. 2006, Issue 334, pp. tw158
DOI: 10.1126/stke.3342006tw158

HCF-1 (host cell factor-1) is a transcriptional coactivator that is involved in the stimulation of various mammalian genes, as well as the immediate early (IE) genes of herpes simplex virus. HCF-1 interacts with multiple transcriptional regulators and is autocatalytically processed within the nucleus to generate a family of polypeptides that remain associated. Vogel and Kristie showed (using yeast two-hybrid and glutathione S-transferase pull-down experiments) that HCF-1 interacted with the transcriptional regulator four-and-a-half LIM domain-2 (FHL2) through specific regions of the proteolytic processing domain (PPD) of HCF-1. Furthermore, the interaction appeared to be specific for FHL2, because other proteins with LIM domains either did not interact or interacted only weakly. FHL2 preferentially interacted with the noncleaved form of HCF-1, and in a reporter gene assay, a noncleavable mutant of HCF-1 was substantially more effective at stimulating FHL2-dependent gene expression than was the wild-type HCF-1. Thus, in terms of the interaction with FHL2, proteolysis of HCF-1 may serve as a negative regulatory mechanism. However, whether and how HCF-1 autocatalysis is regulated remains to be determined. A reporter gene assay for two different IE gene promoters indicated that FHL2 stimulated expression of those genes in a dose-dependent manner, thereby implicating FHL2 in herpes virus infection.

J. L. Vogel, T. M. Kristie, Site-specific proteolysis of the transcriptional coactivator HCF-1 can regulate its interaction with protein cofactors. Proc. Natl. Acad. Sci. U.S.A. 103, 6817-6822 (2006). [Abstract] [Full Text]