The mammalian COP9 signalosome is an eight-subunit (CSN1-CSN8) complex that plays essential roles in multiple cellular and physiological processes. CSN5 and CSN6 are the only two MPN (Mpr1-Pad1-N-terminal) domain-containing subunits in the complex. Unlike the CSN5 MPN domain, CSN6 lacks a metal-binding site and isopeptidase activity. Here, we report the crystal structure of the human CSN6 MPN domain. Each CSN6 monomer contains nine beta sheets surrounded by three helices. Two forms of dimers are observed in the crystal structure. Interestingly, a domain swapping of beta 8 and beta 9 strands occurs between two neighboring monomers to complete a typical MPN fold. Analyses of the pseudo metal-binding motif in CSN6 suggest that the loss of two key histidine residues may contribute to the lack of catalytic activity in CSN6. Comparing the MPN domain of our CSN6 with that in the CSN complex shows that apart from the different beta 8-beta 9 conformation, they have minor conformational differences at two insertion regions (Ins-1 and Ins-2). Besides, the interacting mode of CSN6-CSN6 in our structure is distinct from that of CSN5-CSN6 in the CSN complex structure. Moreover, the functional implications for Ins-1 and Ins-2 are discussed. (C) 2014 Elsevier Inc. All rights reserved.