2014.12.15 Folding and dimerization of the “intrinsically disordered” cytoplasmic domain of ADAM10 in the membrane

2019-07-07 00:18:51 0

定量生物学中心

学术报告

 

题目: Folding and dimerization of the “intrinsically disordered” cytoplasmic domain of ADAM10 in the membrane environment

报告人: 邓巍博士

             Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA

时间:2014-12-15(周一),13:00-14:00

地点:北京大学老化学楼东配楼102会议室

主持人:定量生物学中心,来鲁华教授

Abstract

ADAM10, a sheddase of A Disintegrin And Metalloprotease family, plays a central role in cell proliferation and communication as it regulates the releasing of extracellular domains for numerous membrane receptors in a process named “ectodomain shedding”.  Alternation of the ADAM10’s activity has been diagnosed in patients with pancreatic cancers and Alzheimer diseases, suggesting a potential therapeutic strategy against these diseases by manipulation of ADAM10’s activity.  Latest discovery indicated that ADAM10’s activity appeared to be regulated by a homodimerization mechanism requiring its cytoplasmic domain.  The mechanism underlying such dimerization remains unknown since ADAM10’s cytoplasmic region is enriched with proline and lack of bulk residues, making it an “intrinsically disordered region” based on current knowledge of protein folding. Indeed we found the isolated cytoplasmic domain of ADAM10 is unstructured and lack of any homomeric association. However, once the cytoplasmic domain of ADAM10 is conjunct with its transmembrane domain it become folded and forms a strong homodimer in a membrane environment. A strong and specific dimerization signal from a transcriptional-based reporter assay was observed as placing the transmembrane and cytoplasmic domains of ADAM10, but not the transmembrane domain alone, in the inner membrane of Escherichia coli in their native orientation. Overall, these results reveal a novo feature of the intrinsically disordered cytoplasmic domain of ADAM10 to form a homodimer in a membrane environment. This finding may advance our understanding of the regulatory mechanism of ADAMs and has general implications for membrane-protein interactions in the process of transmembrane signaling.