Abstract
BackgroundCisd1 and Cisd2 proteins share very similar structures with an N-terminal membrane-anchoring domain and a C-terminal cytosolic domain containing an iron-cluster binding domain and ending with a C-terminal KKxx sequence. Despite sharing a similar structure, Cisd1 and Cisd2 are anchored to different compartments: mitochondria for Cisd1 and endoplasmic reticulum for Cisd2. The aim of this study was to identify the protein motifs targeting Cisd2 to the ER and ensuring its retention in this compartment.ResultsWe used new recombinant antibodies to localize Cisd1 and Cisd2 proteins, as well as various protein chimeras. Cisd2 is targeted to the ER by its N-terminal sequence. It is then retained in the ER by the combined action of a C-terminal COPI-binding KKxx ER retrieval motif, and of an ER-targeting transmembrane domain. As previously reported for Cisd1, Cisd2 can alter the morphology of the compartment in which it accumulates.ConclusionAlthough they share a very similar structure, Cisd1 and Cisd2 use largely different intracellular targeting motifs to reach their target compartment (mitochondria and endoplasmic reticulum, respectively).
Highlights
Cisd1 and Cisd2 proteins share very similar structures with an N-terminal membrane-anchoring domain and a C-terminal cytosolic domain containing an iron-cluster binding domain and ending with a C-terminal KKxx sequence
The situation is less clear for Cisd2 which has been proposed to be anchored to the endoplasmic reticulum (ER) [1,2,3] or to mitochondria [4]
The N-terminal region of Cisd1 and Cisd2 targets them to mitochondria and the endoplasmic reticulum, respectively The primary targeting of proteins during or shortly after their translation is often controlled by their N-terminal sequence
Summary
Cisd and Cisd proteins share very similar structures with an N-terminal membrane-anchoring domain and a C-terminal cytosolic domain containing an iron-cluster binding domain and ending with a C-terminal KKxx sequence. Despite sharing a similar structure, Cisd and Cisd are anchored to different compartments: mitochondria for Cisd and endoplasmic reticulum for Cisd. The CDGSH domain binds (Fe2S2) iron-sulfur clusters. It is found in three human proteins: Cisd ( referred to as mitoNEET), Cisd (Miner; NAF-1) and Cisd (Miner). Cisd and Cisd are the most studied members of the family and have a very similar organization: their N-terminal portion contains a transmembrane domain (TMD), and the CDGSH domain is located in the cytosol, where it forms a dimer. The situation is less clear for Cisd which has been proposed to be anchored to the endoplasmic reticulum (ER) [1,2,3] or to mitochondria [4].
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