The mammalian DUF59 protein Fam96a forms two distinct types of domain-swapped dimer.
Fam96a mRNA, which encodes a mammalian DUF59 protein, is enriched in macrophages. Recombinant human Fam96a forms stable monomers and dimers in solution. Crystal structures of these two forms revealed that each adopts a distinct type of domain-swapped dimer, one of which is stabilized by zinc binding. Two hinge loops control Fam96a domain swapping; both are flexible and highly conserved, suggesting that domain swapping may be a common feature of eukaryotic but not bacterial DUF59 proteins. The derived monomer fold of Fam96a diverges from that of bacterial DUF59 counterparts in that the C-terminal region of Fam96a is much longer and is positioned on the opposite side of the N-terminal core fold. The putative metal-binding site of bacterial DUF59 proteins is not conserved in Fam96a, but Fam96a interacts tightly in vitro with Ciao1, the cytosolic iron-assembly protein. Moreover, Fam96a and Ciao1 can be co-immunoprecipitated, suggesting that the interaction also occurs in vivo. Although predicted to have a signal peptide, it is shown that Fam96a is cytoplasmic. The data reveal that eukaryotic DUF59 proteins share intriguing characteristics with amyloidogenic proteins.
Institute for Molecular Bioscience, Division of Chemistry and Structural Biology, University of Queensland, Brisbane, Queensland 4072, Australia.
Kai En
KE
Chen
Ayanthi A
AA
Richards
Juliana K
JK
Ariffin
Ian L
IL
Ross
Matthew J
MJ
Sweet
Stuart
S
Kellie
Bostjan
B
Kobe
Jennifer L
JL
Martin
D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D006367:HeLa Cells; D006801:Humans; D056511:Metallochaperones / Q000378:metabolism; D008667:Metalloproteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D040681:Structural Homology, Protein
C112111:CIAO1 protein, human; C574944:CIAO2A protein, human; D002352:Carrier Proteins; C574945:Ciao2a protein, mouse; D056511:Metallochaperones; D008667:Metalloproteins; D012333:RNA, Messenger