亨廷顿结合蛋白HYPB与脯氨酸丰富区的相互作用和调节机制

Huntington's disease (HD) is caused by polyglutamine (PolyQ) expansion in the N-terminus of huntingtin (htt), however, the detailed pathogenesis remain unknown. Faber et.al.found HYPB（huntingtin yeast partner B）interact with Htt through their WW domain and PRR(Proline-Rich-Region) respectively using yeast two hybrid approach. The interactions are very important for the normal functions of Htt and the onset of Huntington's disease. HYPB contain two PRR except its WW domain, our recent work indicate the PRR which is close to the WW domain interact with WW domain, so we speculate that the interaction between HYBP WW domain and PRR regulate the interaction between HYPB WW domain and Htt PRR.This project studies the interactions and potential regulatory mechanism between HYPB WW domain and Htt PRR. The project will be helpful for understanding the normal functions of Htt and the relations between Htt aggregation and Huntington's disease.

亨廷顿舞蹈症是由于亨廷顿蛋白（Hungtintin；Htt）氨基端的多聚谷氨酰胺（Polyglutamine；PolyQ）的延长突变造成的，具体的致病机理现在还不清楚。Faber等人通过酵母双杂交方法发现HYPB（huntingtin yeast partner B）能够通过其WW结构域与Htt的脯氨酸丰富区（Proline-Rich-Region；PRR）相互作用，而且该相互作用对于Htt的正常功能以及亨廷顿舞蹈症的发生至关重要。HYPB自身也含有两个PRR区域，我们最近的工作发现靠近WW结构域的一段PRR能够与WW结构域发生相互作用，因此推测该相互作用会调节HYPB的WW结构域与Htt PRR之间的相互作用。本项目研究HYPB的WW结构域与Htt的PRR的相互作用和调节机制，阐明该相互作用的结构基础，以便加深了解Htt蛋白的正常生物学功能，Htt异常积聚与亨廷顿舞蹈症之间的关系

本项目研究亨廷顿蛋白（Htt）与亨廷顿结合蛋白HYPB和HYPC的相互作用及与Htt蛋白异常积聚的关系。我们的研究发现HYPB/SETD2蛋白的WW结构域和HYPC 的双WW结构域受附近多聚脯氨酸PolyP肽段调节，并存在自抑制现象，该自抑制作用调节HYPB和HYPC与Htt 中的脯氨酸丰富区PRR的相互作用。这为PolyQ延伸的Htt蛋白的异常积聚提出了一种新的调节模式。