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J. Biol. Chem., Vol. 280, Issue 17, 16676-16684, April 29, 2005

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The LH Gene of Several Mammals Embeds a Carboxyl-terminal Peptide-like Sequence Revealing a Critical Role for Mucin Oligosaccharides in the Evolution of Lutropin to Chorionic Gonadotropin in the Animal Phyla^*

Sigal Nakav, Albina Jablonka-Shariff, Shelly Kaner, Prabhjit Chadna-Mohanty¶, H. Edward Grotjan¶, and David Ben-Menahem||

From the Department of Clinical Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel, the Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110, and the ^¶Department of Animal Science, University of Nebraska, Lincoln, Nebraska 68583

The expression of a previously untranslated carboxylterminal sequence is associated with the ancestral lutropin (LH) to the -subunit gene evolution of choriogonadotropins (CG). The peptide extension (denoted as CTP) is rich in mucin-type O-glycans and confers new hormonal properties on CG relative to the LH. Although the LH gene is conserved among mammals and only a few frameshift mutations account for the extension, it is merely seen in primates and equids. Bioinformatics identified a CTP-like sequence that is encrypted in the LH gene of several mammalian species but not in birds, amphibians, or fish. We then examined whether or not decoding of the cryptic CTP in the bovine LH gene (boCTP) would be sufficient to generate the LH species of a ruminant with properties typical to the CG subunit. The mutated bovine LH-boCTP subunit was expressed and N-glycosylated in transfected Chinese hamster ovary cells. However, unlike human (h) CG CTP, the cryptic boCTP was devoid of mucin O-glycans. This deficiency was further confirmed when the boCTP domain was substituted for the natural CTP in the human CG subunit. Moreover, when expressed in polarized Madin-Darby canine kidney cells, this hCG-boCTP chimera was secreted basolaterally rather than from the apical compartment, which is the route of the wild type hCG subunit, a sorting function attributed to the O-glycans attached to the CTP. This result shows that the cryptic peptide does not orientate CG to the apical face of the placenta, to the maternal circulation as seen in primates. The absence of this function, which distinguishes CG from LH, provides an explanation as to why the LH to CG evolution did not occur in ruminants. We propose that in primates and equids, further natural mutations in the progenitor LH gene resulted in the efficient O-glycosylation of the CTP, thus favoring the retention of an elongated reading frame.

Received for publication, January 20, 2005 , and in revised form, February 18, 2005.

^* This work was supported in part by a grant from the United States Department of Agriculture (to H. E. G.), the Israel Science Foundation and The Charles H. Revson Foundation (to D. B.-M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed. Tel.: 972-8-6477485; Fax: 972-8-6477629; E-mail: dbm{at}bgumail.bgu.ac.il.

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