Structural mechanisms of DIAP1 auto-inhibition and DIAP1-mediated inhibition of drICE

Xiaochun Li, Jiawei Wang and Yigong Shi ()
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Xiaochun Li: Ministry of Education Protein Science Laboratory, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University
Jiawei Wang: Ministry of Education Protein Science Laboratory, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University
Yigong Shi: Ministry of Education Protein Science Laboratory, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University

Nature Communications, 2011, vol. 2, issue 1, 1-9

Abstract: Abstract The Drosophila inhibitor of apoptosis protein DIAP1 exists in an auto-inhibited conformation, unable to suppress the effector caspase drICE. Auto-inhibition is disabled by caspase-mediated cleavage of DIAP1 after Asp20. The cleaved DIAP1 binds to mature drICE, inhibits its protease activity, and, presumably, also targets drICE for ubiquitylation. DIAP1-mediated suppression of drICE is effectively antagonized by the pro-apoptotic proteins Reaper, Hid, and Grim (RHG). Despite rigorous effort, the molecular mechanisms behind these observations are enigmatic. Here we report a 2.4 Å crystal structure of uncleaved DIAP1–BIR1, which reveals how the amino-terminal sequences recognize a conserved surface groove in BIR1 to achieve auto-inhibition, and a 3.5 Å crystal structure of active drICE bound to cleaved DIAP1–BIR1, which provides a structural explanation to DIAP1-mediated inhibition of drICE. These structures and associated biochemical analyses, together with published reports, define the molecular determinants that govern the interplay among DIAP1, drICE and the RHG proteins.

Date: 2011
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DOI: 10.1038/ncomms1418

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