1a93

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NMR SOLUTION STRUCTURE OF THE C-MYC-MAX HETERODIMERIC LEUCINE ZIPPER, NMR, MINIMIZED AVERAGE STRUCTURE

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

The oncoprotein c-Myc (a member of the helix-loop-helix-leucine zipper, (b-HLH-LZ) family of transcription factors) must heterodimerize with the, b-HLH-LZ Max protein to bind DNA and activate transcription. It has been, shown that the LZ domains of the c-Myc and Max proteins specifically form, a heterodimeric LZ at 20 degreesC and neutral pH. This suggests that the, LZ domains of the c-Myc and Max proteins are playing an important role in, the heterodimerization of the corresponding gene products in vivo., Initially, to gain an insight into the energetics of heterodimerization, we studied the stability of N-terminal disulfide-linked versions of the, c-Myc and Max homodimeric LZs and c-Myc-Max heterodimeric LZ by fitting, the temperature-induced denaturation curves monitored by circular, dichroism spectroscopy. The c-Myc LZ does not homodimerize (as previously, reported) and the c-Myc-Max heterodimeric LZ is more stable than the Max, homodimeric LZ at 20 degreesC and pH 7.0. In order to determine the, critical interhelical interactions responsible for the molecular, recognition between the c-Myc and Max LZs, the solution structure of the, disulfide-linked c-Myc-Max heterodimeric LZ was solved by two-dimensional, 1H-NMR techniques at 25 degreesC and pH 4.7. Both LZs are alpha-helical, and the tertiary structure depicts the typical left-handed super-helical, twist of a two-stranded parallel alpha-helical coiled-coil. A buried salt, bridge involving a histidine on the Max LZ and two glutamate residues on, the c-Myc LZ is observed at the interface of the heterodimeric LZ. A, buried H-bond between an asparagine side-chain and a backbone carbonyl is, also observed. Moreover, evidence for e-g interhelical salt bridges is, reported. These specific interactions give insights into the preferential, heterodimerization process of the two LZs. The low stabilities of the Max, homodimeric LZ and the c-Myc-Max heterodimeric LZ as well as the specific, interactions observed are discussed with regard to regulation of, transcription in this family of transcription factors.

Disease

Known disease associated with this structure: Burkitt lymphoma OMIM:[190080]

About this Structure

1A93 is a Protein complex structure of sequences from Homo sapiens and Mus musculus with ACE and NH2 as ligands. Full crystallographic information is available from OCA.

Reference

Insights into the mechanism of heterodimerization from the 1H-NMR solution structure of the c-Myc-Max heterodimeric leucine zipper., Lavigne P, Crump MP, Gagne SM, Hodges RS, Kay CM, Sykes BD, J Mol Biol. 1998 Aug 7;281(1):165-81. PMID:9680483

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