Schuck Stephen, Stenlund Arne
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA
J Virol. 2015 Jan 15;89(2):1129-42. doi: 10.1128/JVI.01903-14. Epub 2014 Nov 5.
Viruses frequently combine multiple activities into one polypeptide to conserve coding capacity. This strategy creates regulatory challenges to ascertain that the combined activities are compatible and do not interfere with each other. The papillomavirus E1 protein, as many other helicases, has the intrinsic ability to form hexamers and double hexamers (DH) that serve as the replicative DNA helicase. However, E1 also has the more unusual ability to generate local melting by forming a double trimer (DT) complex that can untwist the double-stranded origin of DNA replication (ori) DNA in preparation for DH formation. Here we describe a switching mechanism that allows the papillomavirus E1 protein to form these two different kinds of oligomers and to transition between them. We show that a conserved regulatory module attached to the E1 helicase domain blocks hexamer and DH formation and promotes DT formation. In the presence of the appropriate trigger, the inhibitory effect of the regulatory module is relieved and the transition to DH formation can occur.
This study provides a mechanistic understanding into how a multifunctional viral polypeptide can provide different, seemingly incompatible activities. A conserved regulatory sequence module attached to the AAA+ helicase domain in the papillomavirus E1 protein allows the formation of different oligomers with different biochemical activities.
病毒经常将多种活性整合到一个多肽中以节省编码能力。这种策略带来了调控挑战，以确保整合的活性相互兼容且不相互干扰。乳头瘤病毒E1蛋白与许多其他解旋酶一样，具有形成六聚体和双六聚体（DH）的内在能力，这些六聚体和双六聚体可作为复制性DNA解旋酶。然而，E1还具有更不寻常的能力，即通过形成双三聚体（DT）复合物来产生局部解链，该复合物可以解开DNA复制起始位点（ori）的双链DNA，为DH的形成做准备。在这里，我们描述了一种转换机制，该机制允许乳头瘤病毒E1蛋白形成这两种不同类型的寡聚体并在它们之间转换。我们表明，附着在E1解旋酶结构域上的保守调控模块会阻止六聚体和DH的形成，并促进DT的形成。在存在适当触发因素的情况下，调控模块的抑制作用会解除，从而可以发生向DH形成的转变。
本研究提供了一种机制性理解，即多功能病毒多肽如何能够提供不同的、看似不兼容的活性。乳头瘤病毒E1蛋白中附着在AAA+解旋酶结构域上的保守调控序列模块允许形成具有不同生化活性的不同寡聚体。
