Helical filament structure of the DREP3 CIDE domain reveals a unified mechanism of CIDE-domain assembly.

So Yeon Lee,Sunghark Kwon,Hyun Ji Ha,Hyun Ho Park,Sung Hoon Lee

doi:10.1107/s2059798321010767

Abstract

The cell-death-inducing DFF45-like effector (CIDE) domain is a protein-interaction module comprising ∼80 amino acids and was initially identified in several apoptotic nucleases and their regulators. CIDE-domain-containing proteins were subsequently identified among proteins involved in lipid metabolism. Given the involvement of CIDE-domain-containing proteins in cell death and lipid homeostasis, their structure and function have been intensively studied. Here, the head-to-tail helical filament structure of the CIDE domain of DNA fragmentation factor-related protein 3 (DREP3) is presented. The helical filament structure was formed by opposing positively and negatively charged interfaces of the domain and was assembled depending on protein and salt concentrations. Although conserved filament structures are observed in CIDE family members, the structure elucidated in this study and its comparison with previous structures indicated that the size and the number of molecules used in one turn vary. These findings suggest that this charged-surface-based head-to-tail helical filament structure represents a unified mechanism of CIDE-domain assembly and provides insight into the function of various forms of the filament structure of the CIDE domain in higher-order assembly for apoptotic DNA fragmentation and control of lipid-droplet size.

Highlights

DNA fragmentation into a laddered pattern comprising multiples of 180–200 base-pair fragments is a biochemical hallmark of apoptotic cells (Nagata, 2000; Batistatou & Greene, 1993; Enari et al, 1998)
The cell death-inducing DFF45-like effector (CIDE) domain is a conserved protein-interaction module found in several proteins involved in cell death and lipid metabolism (Fig. 1a)
CIDE-domain-mediated DNA-fragmentation factor of 40 kDa (DFF40) and DFF45 interactions are important for regulating the nuclease activity of DFF40 during apoptotic DNA fragmentation

Summary

Introduction

DNA fragmentation into a laddered pattern comprising multiples of 180–200 base-pair (bp) fragments is a biochemical hallmark of apoptotic cells (Nagata, 2000; Batistatou & Greene, 1993; Enari et al, 1998). A previous study reported that DREP2 acts as a synaptic protein and exhibits a unique function in learning and behavioural adaptation (Andlauer et al, 2014). Another family of CIDE-containing proteins includes CIDE-A, CIDE-B and FSP27 ( known as CIDE-C), which play roles in lipid metabolism at the lipid-droplet level rather than in apoptotic DNA fragmentation (Xu et al, 2012; Traini & Jessup, 2009; Yonezawa et al, 2011). Functional failure of CIDE-domaincontaining proteins has been linked to obesity, diabetes, liver steatosis and cardiovascular diseases (Xu et al, 2012)

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Conclusion