Nucleotide exchange factor SIL1 is a protein that in humans is encoded by the SIL1 gene. This gene encodes a resident endoplasmic reticulum (ER), N-linked glycoprotein with an N-terminal ER targeting sequence, 2 putative N-glycosylation sites, and a C-terminal ER retention signal. This protein functions as a nucleotide exchange factor for another unfolded protein response protein. Mutations in this gene have been associated with Marinesco-Sjogren syndrome. Alternate transcriptional splice variants have been characterized. Discovery and expression In the mid-1990s, several laboratories independently discovered Sil1 in three different organisms. A conditional lethality screen was used in the yeast Yarrowia lipolytica to detect cellular components that interacted with the 7S RNA or the signal recognition particle (SRP) during co-translational translocation, which led to the identification of the Sls1p gene. Sls1p is an ER-luminal, 54 kDa protein that contains an N-terminal signal sequence and a C-terminal ER-retention motif. Sls1p fractionated with the membranous fraction and was shown to interact with the Sec61p translocation apparatus. Sls1p was induced by ER stresses, such as heat shock or inhibition of glycosylation, and its deletion resulted in decreased maturation of secretory proteins. This protein also bound to the ADP-bound form of Kar2p, the yeast homolog of BiP, and stimulated its interaction with Sec63, a DnaJ family member and a translocon component. Disruption of the interaction between Sls1p and Kar2p significantly affected the secretion of a reporter protein, leading the investigators to conclude that Sls1p assisted BiP in the translocation of nascent proteins into the ER lumen. Another group working with Saccharomyces cerevisiae conducted a screen for genes that would suppress the severe growth defect observed in the ΔIre1ΔLhs1 yeast double mutants when overexpressed and named this gene the suppressor of Ire1 and Lhs1 deletion 1 (Sil1). Sil1p was shown to be a homolog of Sls1p, and a combined deletion of Sil1p and Lhs1 (yeast GRP170) proved to be lethal after causing a total block in protein translocation into the ER. Mammalian (human) SIL1 was discovered in a yeast two-hybrid screen aimed at identifying proteins that interacted with a mutant ATPase domain of BiP and was initially named BiP-associated protein (BAP). Sequence analysis revealed that BAP is a mammalian homolog of Sls1p and Sil1p and is similar to the cytosolic HSP70-binding protein, HSPBP1. Biochemical data further demonstrated that BAP also had NEF activity for BiP. Structure and mechanism of nucleotide exchange Structural data for yeast Sil1p revealed an