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JBC:改变DNA包装方式对抗白血病

来源:科学网 2008-10-29 13:18

白血病是一种由骨髓中的白细胞反常生产而导致的癌症,每年有数以万计的人患病。当前的治疗主要依赖于杀灭癌细胞,但同时也会破坏正常细胞。美国科学家近日发现了一种新方法,能够破坏作为白细胞生产过程关键部件的蛋白开关。这一发现可能带来对某些白血病更为有效的疗法,并革新其它癌症的治疗方法。相关论文发表在《生物化学杂志》(JBC)上。

美国雪城大学(Syracuse University)的Michael Cosgrove和同事花了3年的时间研究一种混合谱系白血病(MLL)蛋白,它包含3969个氨基酸,调控白细胞形成时DNA的包装方式。在正常细胞中,它与另外3种蛋白结合,形成分子开关控制着DNA的包装。在一些类型的白血病中,MLL开关被破坏,阻止了白细胞的正确成熟,导致了不成熟白细胞的危险增殖。

研究人员鉴别出了MLL蛋白的一个微小组分——仅包含6个氨基酸的肽序列,该序列负责在正常细胞中装配MLL分子开关。研究人员发现,人工合成的该序列像药物一样,能够分解MLL分子开关,中断白细胞生产所必需的酶过程,从而能够减慢或阻止反常白细胞的形成。研究人员称,这一肽序列可能能够帮助重组DNA在白血病细胞中的包装方式,并将反常细胞逆转回正常细胞。

Cosgrove说:“在癌细胞中改变DNA的包装方式是一种崭新的思路,或许将导致副作用更少的更好疗法。我们希望,随着对这些DNA包装蛋白工作机制的进一步了解,人们能够找到新方法来治疗所有类型的白血病以及其它疾病。”(生物谷Bioon.com)

生物谷推荐原始出处:

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.

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