Complexity and Specificity of Sec61-Channelopathies: Human Diseases Affecting Gating of the Sec61 Complex
Abstract
:1. Introduction
2. The Human Sec61 Translocon
2.1. Entry of Precursor Polypeptides into the ER
2.2. Targeting of Precursor Polypeptides to the ER
2.3. Structure of the Sec61 Complex
2.4. Dynamics of the Sec61 Complex
2.5. Auxiliary Factors of the Sec61 Complex
2.5.1. Allosteric Effectors of the Sec61 Channel for Channel Opening
2.5.2. Additional Auxiliary Factors of the Sec61 Complex
2.5.3. Structural Considerations
3. Gating of the Sec61 Channel by BiP
3.1. Structure and Dynamics of BiP
3.2. BiP and Sec62 as Allosteric Effectors of the Sec61 Complex for Channel Closing
4. Sec61-Channelopathies
4.1. Bacterial and Fungal Toxins That Target the Sec61 Channel
4.2. Mutated Variants of the Sec61 Channel
4.2.1. Sec61α 1 p.V67G and p.T185A in ADTKD
4.2.2. Sec61α 1 p.Q92R and p.V67G in ADSCN
4.2.3. Sec61α 1 p.V85D and p.E381* in CVID
4.2.4. Sec61α1 p.Y344H in Mice in Diabetes mellitus
5. Diseases That Are Related to Allosteric Effectors of the Sec61 Channel
5.1. Loss of TRAP Function in Congenital Disorders of Glycosylation (CDG)
5.2. Sec63 and Sec61β in Autosomal Dominant Polycystic Liver Disease (ADPCLD)
5.3. BiP and Its Co-Chaperones and NEFs in Diabetes and Neurological Disorders
5.3.1. BiP Deficiency in Hemolytic Uremic Syndrome (HUS)
5.3.2. Marinesco–Sjögren Syndrome (MSS)
5.3.3. ERj3 in Polycystic Kidney Disease (PKD)
6. Tumor Diseases That Are Related to the Sec61 Channel
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
AD | Autosomal dominant |
ADP | Adenosine diphosphate |
ATP | Adenosine triphosphate |
BiP | Immunoglobulin heavy chain binding protein |
BS | Binding site |
CaM | Calmodulin |
CDG | Congenital disorder of glycosylation |
CET | Cryo-electron tomography |
CVID | Common variable immunodeficiency |
DNAJ | DnaJ homolog |
EM | Electron microscopy |
EMC | ER membrane complex |
ER | Endoplasmic reticulum |
ERAD | ER-associated (protein) degradation |
ERj | ER (resident) J-domain (protein) |
GBM | Glioblastoma multiforme |
GET | Guided entry of tail-anchored proteins |
GPI | Glycosylphosphatidylinositol |
GRP | Glucose-regulated protein |
GTP | Guanosine triphosphate |
HSP | Heat shock protein |
JDP | J-domain protein |
MSS | Marinesco–Sjögren syndrome |
NBD | Nucleotide-binding domain |
NEF | Nucleotide exchange factor |
OST | Oligosaccharyltransferase |
PAD | Primary antibody deficiency |
PC | Polycystin |
PEX | Peroxisome (protein) |
PKD | Polycystic kidney disease |
PLD | Polycystic liver disease |
RAMP | Ribosome-associated membrane protein |
RCC | Renal cell carcinoma |
RNC | Ribosome-nascent chain complex |
SBD | Substrate-binding domain |
SCND | Severe congenital neutropenia |
SEC | (Protein involved in) secretion |
SERCA | Sarcoplasmic/endoplasmic reticulum ATPase |
SND | SRP-independent |
SP | Signal peptide |
SR | SRP receptor |
SRP | Signal recognition particle |
SSR | Signal sequence receptor |
TA | Tail-anchor(ed) |
TKD | Tubulointerstitial kidney disease |
TMEM | Transmembrane (protein) |
TMH | Transmembrane helix |
TPR | Tetratricopeptide repeat |
TRAM | translocating chain-associating membrane (protein) |
TRAP | Translocon-associated protein |
TRC | Transmembrane recognition complex |
TRX | Thioredoxin |
UPR | Unfolded protein response |
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Component/subunit | Abundance | Location | Linked Diseases |
---|---|---|---|
Calmodulin | 9428 | C | |
Cytosolic Chaperones | C | ||
Hsc70 (HSPA8) | 3559 | ||
Hdj2 (DNAJA1) | 660 | ||
Bag1 (HAP, RAP46) | 46 | ||
#NAC | C | ||
- NACα | 1412 | ||
- NACβ | |||
#SRP | C | ||
- SRP72 | 355 | Aplasia, Myelodysplasia | |
- SRP68 | 197 | ||
- SRP54 | 228 | Neutropenia, Pancreas Insufficiency | |
- SRP19 | 33 | ||
- SRP14 | 4295 | ||
- SRP9 | 3436 | ||
- 7SL RNA | |||
SRP receptor | ERM | ||
- SRα (docking protein) | 249 | ||
- SRβ | 173 | ||
hSnd1 | unknown | ||
Snd receptor | ERM | ||
- hSnd2 (TMEM208) | 81 | ||
- hSnd3 | 49 | ||
#Bag6 complex | C | ||
- TRC35 (Get4) | 171 | ||
- Ubl4A | 177 | ||
- Bag6 (Bat3) | 133 | ||
SGTA | 549 | C | |
TRC40 (Asna1, Get3) | 381 | C | |
TA receptor | ERM | ||
- CAML (CAMLG, Get2) | 5 | ||
- WRB (CHD5, Get1) | 4 | Congenital Heart Disease | |
ERM protein complex | ERM | ||
- EMC1 | 124 | ||
- EMC2 | 300 | ||
- EMC3 | 270 | ||
- EMC4 | 70 | ||
- EMC5 (MMGT1) | 35 | ||
- EMC6 (TMEM93) | 5 | ||
- EMC7 | 247 | ||
- EMC8 | 209 | ||
- EMC9 | 1 | ||
- EMC10 | 3 | ||
#TMCO1 complex | ERM | ||
- TMCO1 ## | 2013 | Glaucoma, Cerebrofaciothoracic Dysplasia | |
- Nicalin | 99 | ||
- TMEM147 | 21 | ||
- CCDC47 (Calumin) | 193 | ||
- NOMO | 267 | ||
PAT complex | ERM | ||
- PAT10 (Asterix) | |||
- CCDC47 (Calumin) | 193 | ||
PEX19 | 80 | C | Zellweger Syndrome |
PEX3 | 103 | ERM | Zellweger Syndrome |
#Sec61 complex ## | ERM | ||
- Sec61α1 | 139 | Diabetes **, CVID, TKD, Neutropenia | |
- Sec61β | 456 | PLD, Colorectal Cancer | |
- Sec61γ | 400 | GBM, Hepatocellular Carcinoma, RCC | |
#Sec62 (TLOC1) | 26 | ERM | Breast-, Prostate-, Cervix-, Lung-Cancer et al. |
ER Chaperones | |||
Sec63 (ERj2) | 168 | ERM | PLD, Colorectal Cancer et al. |
#ERj1 (DNAJC1) | 8 | ERM | |
ERj3 (DNAJB11) | 1001 | ERL | Polycystic Kidney Disease (PKD) |
ERj4 (DNAJB9) | 12 | ERL | |
ERj5 (DNAJC10) | 43 | ERL | |
ERj6 (DNAJC3, p58IPK) | 237 | ERL | Diabetes, Neurodegeneration |
ERj7 (DNAJC25) | 10 | ERM | Hyperinsulinismus, Allergic Asthma |
ERj8 (DNAJC16) | 24 | ERM | |
ERj9 (DNAJC22) | ERM | ||
BiP (Grp78, HSPA5) | 8253 | ERL | Hemolytic Uremic Syndrome (HUS) |
Grp170 (HYOU1) | 923 | ERL | Immunodeficincy & Hypoglycemia |
Sil1 (BAP) | 149 | ERL | Marinesco-Sjögren-Syndrome (MSS) |
Grp94 (CaBP4, Hsp90B1) | 4141 | ERL | |
PPIB (Cyclophilin B) | 1289 | ERL | |
FKBP2 (FKBP13) | 894 | ERL | |
PDIA1 (PDI, ERp59) | 3624 | ERL | Cole-Carpenter Syndrome |
PDIA2 (PDIp) | ERL | ||
PDIA3 (ERp61, Grp57) | 3730 | ERL | |
PDIA4 (ERp72, CaBP2) | 2173 | ERL | |
PDIA5 (PDIR) | 37 | ERL | |
PDIA6 (P5, CaBP1) | 3001 | ERL | |
PDIA9 (ERp29) | ERL | ||
Calreticulin (CaBP3, ERp60) | 14521 | ERL | |
#Calnexinpalmitoylated | 7278 | ERM | |
#TRAM1 | 26 | ERM | |
TRAM2 | 40 | ERM | |
#TRAP complex | ERM | ||
- TRAPα (SSR1) | 568 | ||
- TRAPβ (SSR2) | |||
- TRAPγ (SSR3) | 1701 | CDG, Hepatocellular Carcinoma | |
- TRAPδ (SSR4) | 3212 | CDG | |
#RAMP4 (SERP1) | ERM | ||
#Oligosaccharyltransferase (OST-A) | ERM | ||
- RibophorinI (Rpn1) | 1956 | ||
- RibophorinII (Rpn2) | 527 | ||
- OST48 | 273 | CDG | |
- Dad1 | 464 | ||
- OST4 | |||
- TMEM258 | |||
- Stt3A * | 430 | CDG | |
- DC2 | |||
- Kcp2 | |||
Oligosaccharyltransferase (OST-B) | ERM | ||
- RibophorinI (Rpn1) | 1956 | ||
- RibophorinII (Rpn2) | 527 | ||
- OST48 | 273 | CDG | |
- Dad1 | 464 | ||
- OST4 | |||
- TMEM258 | |||
- Stt3B* | 150 | CDG | |
- TUSC3 | CDG | ||
- MagT1 | 33 | ||
Signal peptidase (SPC-A) | ERM | ||
- SPC12 | 2733 | ||
- SPC18 * (SEC11A) | |||
- SPC22/23 | 334 | ||
- SPC25 | 94 | ||
Signal peptidase (SPC-C) | ERM | ||
- SPC12 | 2733 | ||
- SPC21 * (SEC11C) | |||
- SPC22/23 | 334 | ||
- SPC25 | 94 | ||
GPI transamidase (GPI-T) | ERM | ||
- GPAA1 | 9 | ||
- PIG-K | 38 | ||
- PIG-S | 86 | ||
- PIG-T | 20 | ||
- PIG-U | 42 | ||
Additional modifying enzymes | |||
ALG8 | 10 | ERM | CDG, PLD |
UGGT | 232 | ERL | |
Glucosidase IIα (GIIα) | ERL | PLD | |
Glucosidase IIβ (PRKCSH, GIIβ) | ERL | PLD | |
Proly-4-hydroxylase α (4-PH) | ERL | ||
Proly-4-hydroxylase β (PDI) | 3624 | ERL | Cole-Carpenter Syndrome |
SUMF1 | 23 | ERL | Multiple Sulfatase Deficiency |
SUMF2 | 386 | ERL | Multiple Sulfatase Deficiency |
#p34 (LRC59, LRRC59) | 2480 | ERM | |
#p180 (RRBP1) | 135 | ERM | Hepatocellular Carcinoma, Colorectal Cancer |
Kinectin 1 (KTN1) | 263 | ERM |
Inhibitor | Binding Site in Sec61α | Effect | Linked Disease(s) |
---|---|---|---|
Apratoxin A | T86 (TMH2), Y131 (TMH5) | non-selective | |
CAM741 | selective inhibition | ||
Coibamide A | non-selective | ||
Cotransin CT8 | R66 (loop 1), G80 (TMH2), S82 (loop 1), M136 (TMH3) | selective inhibition | |
Eeyarestatin ES24 | non-selective Ca2+ leak inducing | ||
Exotoxin A | N-terminus | non-selective Ca2+ leak blocking | Pneumonia, Sepsis |
Ipomoeassin F | non-selective | ||
Mycolactone | R66 (loop 1), S82 (loop 1) | selective inhibition Ca2+ leak inducing | Buruli ulcer |
Disease | Linked Gene(s) | Sec61 Effect | MIM |
---|---|---|---|
ADPKD | DNAJB11 | Ca2+ leak induction * | |
PKD1, PKD2, UMOD | |||
ADPLD | ALG8, GANAB, PRKCSH, | ||
SEC61B, SEC63 | selective transport inhibition | 617004 | |
ADSCN | ELANE, JAGN1, SEC61A1 | transport inhibition | |
Ca2+ leak induction | |||
ADTKD | HNF1B, MUC1, REN, | selective transport inhibition | |
SEC61A1, UMOD | Ca2+ leak induction | 617056 | |
CDG | ALG8, SSR3, SSR4, OST48, | selective transport inhibition | |
STT3A, STT3B, TUSC3 | |||
CVID | CD19, CD20, CD21, | transport inhibition | |
CD80, SEC61A1 | Ca2+ leak induction | ||
Diabetes | DNAJC3, INS | Ca2+ leak induction * | |
MSS | SIL1 | 248800 |
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Sicking, M.; Lang, S.; Bochen, F.; Roos, A.; Drenth, J.P.H.; Zakaria, M.; Zimmermann, R.; Linxweiler, M. Complexity and Specificity of Sec61-Channelopathies: Human Diseases Affecting Gating of the Sec61 Complex. Cells 2021, 10, 1036. https://doi.org/10.3390/cells10051036
Sicking M, Lang S, Bochen F, Roos A, Drenth JPH, Zakaria M, Zimmermann R, Linxweiler M. Complexity and Specificity of Sec61-Channelopathies: Human Diseases Affecting Gating of the Sec61 Complex. Cells. 2021; 10(5):1036. https://doi.org/10.3390/cells10051036
Chicago/Turabian StyleSicking, Mark, Sven Lang, Florian Bochen, Andreas Roos, Joost P. H. Drenth, Muhammad Zakaria, Richard Zimmermann, and Maximilian Linxweiler. 2021. "Complexity and Specificity of Sec61-Channelopathies: Human Diseases Affecting Gating of the Sec61 Complex" Cells 10, no. 5: 1036. https://doi.org/10.3390/cells10051036