Dec 9: Tumor Suppressor Menin and its Related Factors: Structures, Regulatory Mechanisms, and Tumorigenesis
Speaker：Jing Huang
Host: Prof. Jiemin Wong
When: 2013-12-9 10:00
Where: Conference Room 534, School of Life Sciences
Abstract: Menin is a tumor suppressor protein whose loss or inactivation causes multiple endocrine neoplasia 1 syndrome (MEN1). It interacts with many proteins and is involved in a variety of cellular pathways. Menin binds the Jun family transcription factor JunD and inhibits JunD-mediated transcription activation. It also interacts with the histone H3K4 methyltransferase MLL1 and functions as a cofactor to upregulate gene transcription or to promote MLL1-fusion-protein-induced leukaemogenesis. Inhibitors targeted at the menin-MLL1 interaction could efficiently reverse oncogenic activity of MLL1 fusion proteins in leukemia. We resolved the crystal structures of human menin in its free form and in complex with MLL1 or with JunD, or with an MLL1-LEDGF heterodimer. These structures show that menin contains a deep pocket that binds short peptides of JunD or MLL1 in the same manner but can have opposite effects on gene transcription regulation. The menin-JunD interaction blocks the docking of JNK on JunD and suppresses JunD-induced transcription. In contrast, menin binds MLL1 through the deep pocket while still interacts with the chromatin-anchoring protein LEDGF at a distinct surface formed by both menin and MLL1, and hence acts as a scaffold protein to target MLL1 for gene transcription activation. Based on the menin-MLL1 crystal structure, we designed high-affinity macrocyclic peptidomimetic inhibitors to target the menin-MLL1 interaction in leukemia. The most potent inhibitor binds to menin with a Ki value of 4.7 nM and serves as a promising lead structure for the design of potent and cell-permeable inhibitors of the menin-MLL1 interaction. In addition, we also studied the crystal structure of the telomerase ribonucleoprotein complex. Telomerase is repressed by menin and several other tumor suppressors in most somatic cells but is reactivated in essentially all tumor types, and thus has been studied as a plausible anti-cancer target. It is a large ribonucleoprotein complex minimally composed of a catalytic telomerase reverse transcriptase (TERT) and an RNA component (TR) that provides the template for telomeric DNA synthesis. However, it remains unclear how TERT and TR assemble into a functional telomerase complex. We report the first crystal structure of the conserved regions 4 and 5 (CR4/5) of vertebrate TR in complex with the TR-binding domain (TRBD) of TERT. The structure shows that the CR4/5 RNA adopts an L-shaped three-way junction conformation with its two arms clamping onto TRBD. Both sequence and the conformation of CR4/5 are required for the interaction. Our structural and mutational analyses suggests that the observed CR4/5-TRBD recognition is common to species from yeast to humans, and CR4/5 in vertebrate TR might play a similar role in telomerase regulation as stem-loop IV in Tetrahymena TR. Our results also provide structural insights into the architecture of the minimum telomerase catalytic core.