白血病是一種由骨髓中的白細胞反常生產而導致的癌癥，每年有數以萬計的人患病,。當前的治療主要依賴于殺滅癌細胞,，但同時也會破壞正常細胞。美國科學家近日發(fā)現了一種新方法,，能夠破壞作為白細胞生產過程關鍵部件的蛋白開關,。這一發(fā)現可能帶來對某些白血病更為有效的療法，并革新其它癌癥的治療方法,。相關論文發(fā)表在《生物化學雜志》（JBC）上,。

美國雪城大學（Syracuse University）的Michael Cosgrove和同事花了3年的時間研究一種混合譜系白血病（MLL）蛋白,，它包含3969個氨基酸,，調控白細胞形成時DNA的包裝方式。在正常細胞中,，它與另外3種蛋白結合,，形成分子開關控制著DNA的包裝。在一些類型的白血病中,，MLL開關被破壞,，阻止了白細胞的正確成熟，導致了不成熟白細胞的危險增殖,。

研究人員鑒別出了MLL蛋白的一個微小組分——僅包含6個氨基酸的肽序列,，該序列負責在正常細胞中裝配MLL分子開關,。研究人員發(fā)現,，人工合成的該序列像藥物一樣,，能夠分解MLL分子開關，中斷白細胞生產所必需的酶過程,，從而能夠減慢或阻止反常白細胞的形成,。研究人員稱，這一肽序列可能能夠幫助重組DNA在白血病細胞中的包裝方式,，并將反常細胞逆轉回正常細胞,。

Cosgrove說：“在癌細胞中改變DNA的包裝方式是一種嶄新的思路，或許將導致副作用更少的更好療法,。我們希望,，隨著對這些DNA包裝蛋白工作機制的進一步了解，人們能夠找到新方法來治療所有類型的白血病以及其它疾病,。”（生物谷Bioon.com）

生物谷推薦原始出處：

JBC,，doi：10.1074/jbc.M806317200，Anamika Patel,，Michael S. Cosgrove

A conserved arginine containing motif crucial for the assembly and enzymatic activity of the Mixed Lineage Leukemia protein-1 core complex

Anamika Patel, Valarie E. Vought, Venkatasubramanian Dharmarajan, and Michael S. Cosgrove

Biology, Syracuse University, Syracuse, NY 13244

The Mixed Lineage Leukemia protein-1 (MLL1) belongs to the SET1 family of histone H3 lysine 4 methyltransferases. Recent studies indicate that the catalytic subunits of SET1 family members are regulated by interaction with a conserved core group of proteins that include the WD-repeat protein-5 (WDR5), retinoblastoma binding protein-5 (RbBP5), and the Absent small homeotic-2-like protein (Ash2L). It has been suggested that WDR5 functions to bridge the interactions between the catalytic and regulatory subunits of SET1 family complexes. However, the molecular details of these interactions are unknown. To gain insight into the interactions among these proteins we have determined the biophysical basis for the interaction between the human WDR5 and MLL1. Our studies reveal that WDR5 preferentially recognizes a previously unidentified and conserved arginine containing motif- called the “Win” or WDR5 interaction motif, which is located in the N-SET region of MLL1 and other SET1 family members. Surprisingly, our structural and functional studies show that WDR5 recognizes arginine 3765 of the MLL1 Win motif using the same arginine binding pocket on WDR5 that was previously shown to bind histone H3. We demonstrate that WDR5’s recognition of arginine 3765 of MLL1 is essential for the assembly and enzymatic activity of the MLL1 core complex in vitro.

JBC,，doi：10.1074/jbc.C800164200，Anamika Patel,，Michael S. Cosgrove

Structure of WDR5 bound to mixed lineage Leukemia protein-1 peptide

Anamika Patel, Venkatasubramanian Dharmarajan, and Michael S. Cosgrove

Biology, Syracuse University, Syracuse, NY 13244

The Mixed Lineage Leukemia protein-1 (MLL1) catalyzes histone H3 Lysine 4 methylation and is regulated by interaction with WDR5 (WD-repeat protein-5), RbBP5 (Retinoblastoma Binding Protein-5), and the Ash2L (Absent, small, homeotic discs-2-like) oncoprotein. In the accompanying investigation, we describe the identification of a conserved arginine containing motif, called the “Win” or WDR5 interaction motif that is essential for the assembly and H3K4 dimethylation activity of the MLL1 core complex. Here we present a 1.7-? crystal structure of WDR5 bound to a peptide derived from the MLL1 Win motif. Our results show that R3765 of the MLL1 is bound in the same arginine binding pocket on WDR5 that was previously suggested to bind histone H3. Thermodynamic binding experiments show that the MLL1 Win peptide is preferentially recognized by WDR5. These results are consistent with a model in which WDR5 recognizes R3765 of MLL1, which is essential for the assembly and enzymatic activity of the MLL1 core complex.