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Fig. 1 Creb3l1 is a transmembrane transcription factor highly conserved between humans and zebrafish. (A) A schematic of Creb3l1 protein showing the N-terminal transcription activating (TA) region (amino acids 1–374) containing the DNA-binding bZIP domain (amino acids 291–356), followed by a single transmembrane (TM) domain (amino acids 375–395) and the C-terminal luminal domain (amino acids 427–519). The sites cleaved by the S1P and S2P proteases are indicated by arrows. Creb3l1 resides in the endoplasmic reticulum and in response to stress is transported to the Golgi (step 1), where it is cleaved by S1P and S2P proteases (step 2). The released TA fragment then enters the nucleus to regulate transcription of target genes (step 3). (B) Alignment of human and zebrafish Creb3l1. The TA domain is indicated by a blue line and the TM domain is marked by an orange line. The DNA-binding bZIP domain is outlined in red. The sites cleaved by S1P and S2P are boxed in green. The highest level of amino acid conservation is in bZIP, the TM and regions immediately upstream from bZIP. The S1P and S2P cleavage sites also reside within conserved domains. Identical residues are shaded in blue. (C) The genetic loci of human and zebrafish Creb3l1 demonstrate high synteny, sharing 8 genes within the same ~1 megabase span in their respective genomes.