3-Azioctanol Photolabels A Site On The Neural Cell Adhesion Molecule, L1
Arevalo, E; Wilkemeyer, MF; Shanmugasundararaj, S; Charness, ME; Miller, KW
| HERO ID | 1455492 |
|---|---|
| In Press | No |
| Year | 2006 |
| Title | 3-Azioctanol Photolabels A Site On The Neural Cell Adhesion Molecule, L1 |
| Authors | Arevalo, E; Wilkemeyer, MF; Shanmugasundararaj, S; Charness, ME; Miller, KW |
| Journal | Alcoholism: Clinical and Experimental Research |
| Volume | 30 |
| Issue | 6 Suppl |
| Page Numbers | 118A-118A |
| Abstract | Prenatal ethanol exposure results in a spectrum of birth defects and neurobehavioral abnormalities referred to as fetal alcohol spectrum disorders (FASD). One potentially important ethanol target is the L1 neural cell adhesion molecule. L1 is a transmembrane glycoprotein composed of six Ig domains and five fibronectin-type III domains, followed by transmembrane and intracellular domains. Short-chain alcohols (e.g., ethanol and butanol derivatives) show remarkable structural specificity for inhibition of L1-mediated cell adhesion. Other alcohols (e.g., 1-octanol) antagonize ethanol inhibition of L1 cell adhesion and ethanol teratogenesis in mouse whole embryo cultures. To test the hypothesis that there are antagonist binding sites on L1, we have employed the photoactivatable analog of octanol, 3-azioctanol. This agent is remarkably potent at antagonizing ethanol inhibition of L1 adhesion. Azioctanol photoincorporated into a soluble model of L1, consisting of only the six Ig domains. After photolabeling, this polypeptide was digested with trypsin and analyzed by mass spectrometry, which identified Tyr-417 (Y417) and Glu-33 (E33) as sites of photoincorporation. Preliminary modeling of L1, based on the known structure of the homologous 1 and #150;4 Ig domains of axonin-1, suggests that E33 and Y417, on Ig1 and Ig4 respectively, may reside in a single pocket formed by the two Ig domains. Furthermore L120 and G121, in which mutations in humans are associated with neurological disorders, are adjacent to this pocket. Thus, this site likely has functional significance. Identification of the antagonist site will aid in understanding the molecular basis for FASD and may accelerate the development of drugs that block the toxic effects of ethanol on the developing nervous system. |
| Is Certified Translation | No |
| Dupe Override | No |
| Conference Name | 29th Annual Meeting of the Research-Society-on-Alcoholism |
| Conference Date | JUN 23-29, 2006 |
| Is Public | Yes |
| Language Text | eng |