UPF1 Learns to Relax and Unwind Michael L. Gleghorn, Lynne E. Maquat  Molecular Cell  Volume 41, Issue 6, Pages 621-623 (March 2011) DOI: 10.1016/j.molcel.2011.03.001 Copyright © 2011 Elsevier Inc. Terms and Conditions

Figure 1 During NMD, UPF1 Relaxes Its Grip and Manifests Enhanced RNA Helicase Activity When Bound by UPF2 (A) Left: Model of UFP1 interactions and conformations after the SURF (SMG1, UPF1, eRF1, and eRF3) complex forms at a premature termination codon (PTC). When UPF1 is in the “closed” conformation, the cap-binding protein (CBP) 80 contacts part of the UPF1 helicase region (yellow as shown and some gray and red not shown) in a way that is not predicted to interfere with the region of the helicase core that docks the CH domain (light green). eRF3 has been shown to interact with a region of UPF1 that includes the CH domain (Ivanov et al., 2008), and it presumably prefers the closed orientation of this domain. We have positioned SMG1 near the UPF1 C terminus, where it has been shown to phosphorylate UPF1 even though its exact site of binding is unknown. Right: Upon SMG1-UPF1 binding to EJC-bound UPF2, UPF1's strong grip on RNA is released and its helicase activity is enhanced. These actions might simultaneously coordinate the separation of UPF1 from the eRFs, since the binding of UPF2 to UPF1 may compete with the binding of eRF3 to UPF1 (Ivanov et al., 2008). SMG1-UPF1 association with EJC-bound UPF2 promotes the SMG1-mediated phosphorylation of UPF1, which in turn results in UPF1-mediated translational repression and ultimately mRNP remodeling that leads to mRNA decay (Isken, et al., 2008; Franks et al., 2010). Effects of UPF1 phosphorylation on its ATPase and helicase activities have yet to be reported. NTC, normal termination codon. (B) Structural representations of UPF1 in the closed (or tightened) and open (or relaxed) conformations. Representations are of surface models, with cartoon single-stranded RNA (thick black line) and stick ATP. Domains are labeled and color-coded as in (A). Left: The yeast UPF1 closed conformation reported in this issue by Chakrabarti, et al. (2011). Right: A combination model generated by superimposing (using domain 1C) the RNA-bound human UPF1ΔCH structure (Chakrabarti et al., 2011) onto PDB 2WJV (Clerici, et al., 2009), the latter of which includes the human UPF1 CH domain in the open conformation relative to the helicase region, but lacks bound RNA. (C) Diagrams of closed and open configurations of a croll, which is used for rope ascending, as mechanical analogies of, respectively, the UPF2-devoid closed and the UPF2-bound open conformations of UPF1. Parts have been colored according to their functional similarities to the UPF1 domains shown in (B). A croll has no energy-utilizing motor that would be analogous to the helicase region of UPF1. Instead, it would slide down the rope, which in this metaphor is analogous to RNA, once loosened by the user's thumb and forefinger, which are analogous to the bipartite interaction of UPF2 with UPF1 (Clerici, et al., 2009). Left: The safety catch, which is analogous to the UPF1 CH domain, is in the closed position and thereby pushes on the cam (orange), which is analogous to UPF1 domain 1B, to tighten its grip on the rope and keep the device from moving. Right: When the safety catch is opened by the user's thumb and forefinger, the pressure on the cam is released, and the croll's “helicase” activity allows the machine to move forward (5′-to-3′) along the rope. Molecular Cell 2011 41, 621-623DOI: (10.1016/j.molcel.2011.03.001) Copyright © 2011 Elsevier Inc. Terms and Conditions