SIL1

Last updated
SIL1
Identifiers
Aliases SIL1 , BAP, MSS, ULG5, SIL1 nucleotide exchange factor
External IDs OMIM: 608005 MGI: 1932040 HomoloGene: 32544 GeneCards: SIL1
Orthologs
SpeciesHumanMouse
Entrez

64374

81500

Ensembl

ENSG00000120725

ENSMUSG00000024357

UniProt

Q9H173

Q9EPK6

RefSeq (mRNA)

NM_001037633
NM_022464

NM_030749
NM_001360814

RefSeq (protein)

NP_001032722
NP_071909

NP_109674
NP_001347743

Location (UCSC) Chr 5: 138.95 – 139.29 Mb Chr 18: 35.27 – 35.5 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Nucleotide exchange factor SIL1 is a protein that in humans is encoded by the SIL1 gene. [5] [6] [7] [8]

Contents

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. [8]

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. [9] 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 elongated, “kidney bean”-like molecular shape that consists of 16 α-helices (A1–A16) and lacks β-sheets. The central helices A3-A14 form the armadillo (ARM)-like repeats (ARM1-ARM4), which are named after those found in β-catenin. Each ARM repeat is composed of three α-helices that pack into a superhelix. A crystal structure of yeast Sil1p complexed with the ADP-bound NBD of Kar2p/BiP revealed that the ARM domain of Sil1p wraps around lobe IIb of BiP’s NBD and makes additional contacts with lobe Ib. This interaction causes lobes Ib and IIb to rotate away from each other, leading to ADP release. Point mutations in the Sil1p-interacting site of Kar2p’s NBD specifically disrupted Sil1p binding but retained Kar2p’s ability to interact with Lhs1/GRP170, the other ER NEF, providing the first indication that their mechanisms of NEF activity were different. Homology mapping and comparisons with the structure of cytosolic HSPBP1 indicated that the region of SIL1 encoded by exons 6 and 9 constitutes major BiP-binding sites, and exon 10 encodes a minor interaction site.

Tissue expression

Although SIL1 is ubiquitously expressed, levels vary widely by tissue. The Human Protein Atlas (www.proteinatlas.org) shows that the expression pattern of SIL1 mirrors that of BiP even more closely than that of GRP170, which is a known UPR target, as is BiP. Perhaps the different expression pattern for GRP170 is due to its dual function as a chaperone and a NEF for BiP. SIL1 expression at a single-cell level has also been determined in a number of tissues, which does not strictly correlate with the secretory capacity of the cell, and tissues displaying the highest relative levels of SIL1 are not necessarily those most affected by loss of its function. This might imply an additional function, which has been demonstrated for Sil1p, or an as yet undiscovered role of SIL1 in certain tissues. Understanding this reason for variation in tissue expression will require further studies.

SIL1
Identifiers
Aliases SIL1 , BAP, MSS, ULG5, SIL1 nucleotide exchange factor
External IDs OMIM: 608005 MGI: 1932040 HomoloGene: 32544 GeneCards: SIL1
Orthologs
SpeciesHumanMouse
Entrez

64374

81500

Ensembl

ENSG00000120725

ENSMUSG00000024357

UniProt

Q9H173

Q9EPK6

RefSeq (mRNA)

NM_001037633
NM_022464

NM_030749
NM_001360814

RefSeq (protein)

NP_001032722
NP_071909

NP_109674
NP_001347743

Location (UCSC) Chr 5: 138.95 – 139.29 Mb Chr 18: 35.27 – 35.5 Mb
PubMed search [10] [11]
Wikidata
View/Edit Human View/Edit Mouse

Interactions

SIL1 has been shown to interact with Binding immunoglobulin protein. [6]

Related Research Articles

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The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum (RER), and smooth endoplasmic reticulum (SER). The endoplasmic reticulum is found in most eukaryotic cells and forms an interconnected network of flattened, membrane-enclosed sacs known as cisternae, and tubular structures in the SER. The membranes of the ER are continuous with the outer nuclear membrane. The endoplasmic reticulum is not found in red blood cells, or spermatozoa.

Peter Walter

Peter Walter is a German-American molecular biologist and biochemist and Professor at the University of California, San Francisco (UCSF) and a Howard Hughes Medical Institute (HHMI) Investigator

Long-chain-aldehyde dehydrogenase Protein-coding gene in the species Homo sapiens

Fatty aldehyde dehydrogenase is an aldehyde dehydrogenase enzyme that in human is encoded in the ALDH3A2 gene on chromosome 17. Aldehyde dehydrogenase enzymes function to remove toxic aldehydes that are generated by the metabolism of alcohol and by lipid peroxidation.

The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum (ER) stress. It has been found to be conserved between all mammalian species, as well as yeast and worm organisms.

HSP90B1

Heat shock protein 90kDa beta member 1 (HSP90B1), known also as endoplasmin, gp96, grp94, or ERp99, is a chaperone protein that in humans is encoded by the HSP90B1 gene.

ATF6

Activating transcription factor 6, also known as ATF6, is a protein that, in humans, is encoded by the ATF6 gene and is involved in the unfolded protein response.

Binding immunoglobulin protein

Binding immunoglobulin protein (BiP) also known as (GRP-78) or heat shock 70 kDa protein 5 (HSPA5) or (Byun1) is a protein that in humans is encoded by the HSPA5 gene.

BCAP31

B-cell receptor-associated protein 31 is a protein that in humans is encoded by the BCAP31 gene.

EIF2AK3

Eukaryotic translation initiation factor 2-alpha kinase 3, also known as protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), is an enzyme that in humans is encoded by the EIF2AK3 gene.

ERN1

The serine/threonine-protein kinase/endoribonuclease inositol-requiring enzyme 1 α (IRE1α) is an enzyme that in humans is encoded by the ERN1 gene.

SEC61B

Protein transport protein Sec61 subunit beta is a protein that in humans is encoded by the SEC61B gene.

DNAJB11

DnaJ homolog subfamily B member 11 is a protein that in humans is encoded by the DNAJB11 gene.

Derlin-1 Protein involved in retrotranslocation of specific misfolded proteins and in ER stress

Derlin-1 also known as degradation in endoplasmic reticulum protein 1 is a membrane protein that in humans is encoded by the DERL1 gene. Derlin-1 is located in the membrane of the endoplasmic reticulum (ER) and is involved in retrotranslocation of specific misfolded proteins and in ER stress. Derlin-1 is widely expressed in thyroid, fat, bone marrow and many other tissues. The protein belongs to the Derlin-family proteins consisting of derlin-1, derlin-2 and derlin-3 that are components in the endoplasmic reticulum-associated protein degradation (ERAD) pathway. The derlins mediate degradation of misfolded lumenal proteins within ER, and are named ‘der’ for their ‘Degradation in the ER’. Derlin-1 is a mammalian homologue of the yeast DER1 protein, a protein involved in the yeast ERAD pathway. Moreover, derlin-1 is a member of the rhomboid-like clan of polytopic membrane proteins.

KDELR1

KDEL (Lys-Asp-Glu-Leu) endoplasmic reticulum protein retention receptor 1, also known as KDELR1, is a protein which in humans is encoded by the KDELR1 gene.

RRBP1

Ribosome-binding protein 1, also referred to as p180, is a protein that in humans is encoded by the RRBP1 gene.

SEC23A

Sec23 homolog A , also known as SEC23A, is a protein which in humans is encoded by the SEC23A gene.

Sec61 alpha 1

Protein transport protein Sec61 subunit alpha isoform 1 is a protein that in humans is encoded by the SEC61A1 gene.

KDELR2

ER lumen protein retaining receptor 2 is a protein that in humans is encoded by the KDELR2 gene.

UBE2J1

Ubiquitin-conjugating enzyme E2 J1 is a protein that in humans is encoded by the UBE2J1 gene.

Marinesco–Sjögren syndrome (MSS), sometimes spelled Marinescu–Sjögren syndrome, is a rare autosomal recessive disorder.

References

  1. 1 2 3 4 5 6 GRCh38: Ensembl release 89: ENSG00000120725 - Ensembl, May 2017
  2. 1 2 3 4 5 6 GRCm38: Ensembl release 89: ENSMUSG00000024357 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Tyson JR, Stirling CJ (December 2000). "LHS1 and SIL1 provide a lumenal function that is essential for protein translocation into the endoplasmic reticulum". The EMBO Journal. 19 (23): 6440–52. doi:10.1093/emboj/19.23.6440. PMC   305876 . PMID   11101517.
  6. 1 2 Chung KT, Shen Y, Hendershot LM (December 2002). "BAP, a mammalian BiP-associated protein, is a nucleotide exchange factor that regulates the ATPase activity of BiP". The Journal of Biological Chemistry. 277 (49): 47557–63. doi: 10.1074/jbc.M208377200 . PMID   12356756.
  7. ↑ Senderek J, Krieger M, Stendel C, Bergmann C, Moser M, Breitbach-Faller N, et al. (December 2005). "Mutations in SIL1 cause Marinesco-Sjögren syndrome, a cerebellar ataxia with cataract and myopathy". Nature Genetics. 37 (12): 1312–4. doi:10.1038/ng1678. PMID   16282977. S2CID   28860307.
  8. 1 2 "Entrez Gene: SIL1 SIL1 homolog, endoplasmic reticulum chaperone (S. cerevisiae)".
  9. ↑ Ichhaporia VP, Hendershot LM (February 2021). "Role of the HSP70 Co-Chaperone SIL1 in Health and Disease". International Journal of Molecular Sciences. 22 (4): 1564. doi:10.3390/ijms22041564. PMID   33557244.
  10. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  11. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

Further reading

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