Zinc-dependent interaction of transcriptional co-activator CBP/p300 with MTF-1

Abstract

One of the major functions of the metal response element-binding transcription factor 1(MTF-1) is to sense and maintain sub-nanomolar to nanomolar zinc levels in response to influxes of labile zinc within the cell. MTF-1 responses to elevated zinc include up regulation of metallothionein (MT-I & II) and efflux transporter (ZnT1) genes. MTF-1 also responds to oxidative stress and heavy metal loads. Due to a lack of liver development, MTF-1 is essential for embryogenesis as determined from knockout mice. The zinc dependence of DNA-binding and interactions with other transcription factors has been identified as major determinants in the homeostatic regulation of labile intracellular zinc by MTF-1. p300 along with its paralog, cyclic-AMP response element binding protein (CBP), have histone acetyltransferase protein scaffold functions and interact with other transcription factors. Previous studies have shown that p300, Sp1 and MTF-1 form a complex. It was also found that a zinc dependent interaction between p300 and MTF-1 is essential for activation of MT-I transcription in mice. Herein, we present NMR evidence for a physical interaction between MTF-1 and a zinc binding domain of p300. This new observation suggests a complex molecular basis for the zinc dependence of MT-I activation, involving direct zinc coordination to the MTF-1 DNA binding domain and the TAZ2 domain of p300.