| Structural highlights
Disease
CO1A1_HUMAN Defects in COL1A1 are the cause of Caffey disease (CAFFD) [MIM:114000; also known as infantile cortical hyperostosis. Caffey disease is characterized by an infantile episode of massive subperiosteal new bone formation that typically involves the diaphyses of the long bones, mandible, and clavicles. The involved bones may also appear inflamed, with painful swelling and systemic fever often accompanying the illness. The bone changes usually begin before 5 months of age and resolve before 2 years of age.[1] [2] [3] Defects in COL1A1 are a cause of Ehlers-Danlos syndrome type 1 (EDS1) [MIM:130000; also known as Ehlers-Danlos syndrome gravis. EDS is a connective tissue disorder characterized by hyperextensible skin, atrophic cutaneous scars due to tissue fragility and joint hyperlaxity. EDS1 is the severe form of classic Ehlers-Danlos syndrome.[4] [5] [6] [7] Defects in COL1A1 are the cause of Ehlers-Danlos syndrome type 7A (EDS7A) [MIM:130060; also known as autosomal dominant Ehlers-Danlos syndrome type VII. EDS is a connective tissue disorder characterized by hyperextensible skin, atrophic cutaneous scars due to tissue fragility and joint hyperlaxity. EDS7A is marked by bilateral congenital hip dislocation, hyperlaxity of the joints, and recurrent partial dislocations.[8] [9] Defects in COL1A1 are a cause of osteogenesis imperfecta type 1 (OI1) [MIM:166200. A dominantly inherited connective tissue disorder characterized by bone fragility and blue sclerae. Osteogenesis imperfecta type 1 is non-deforming with normal height or mild short stature, and no dentinogenesis imperfecta.[10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] Defects in COL1A1 are a cause of osteogenesis imperfecta type 2 (OI2) [MIM:166210; also known as osteogenesis imperfecta congenita. A connective tissue disorder characterized by bone fragility, with many perinatal fractures, severe bowing of long bones, undermineralization, and death in the perinatal period due to respiratory insufficiency. Defects in COL1A1 are a cause of osteogenesis imperfecta type 3 (OI3) [MIM:259420. A connective tissue disorder characterized by progressively deforming bones, very short stature, a triangular face, severe scoliosis, grayish sclera, and dentinogenesis imperfecta. Defects in COL1A1 are a cause of osteogenesis imperfecta type 4 (OI4) [MIM:166220; also known as osteogenesis imperfecta with normal sclerae. A connective tissue disorder characterized by moderately short stature, mild to moderate scoliosis, grayish or white sclera and dentinogenesis imperfecta. Genetic variations in COL1A1 are a cause of susceptibility to osteoporosis (OSTEOP) [MIM:166710; also known as involutional or senile osteoporosis or postmenopausal osteoporosis. Osteoporosis is characterized by reduced bone mass, disruption of bone microarchitecture without alteration in the composition of bone. Osteoporotic bones are more at risk of fracture.[23] [24] [25] [26] Note=A chromosomal aberration involving COL1A1 is found in dermatofibrosarcoma protuberans. Translocation t(17;22)(q22;q13) with PDGF.[27] [28]
Function
CO1A1_HUMAN Type I collagen is a member of group I collagen (fibrillar forming collagen).SPIKE_SARS2 attaches the virion to the cell membrane by interacting with host receptor, initiating the infection (By similarity). Binding to human ACE2 receptor and internalization of the virus into the endosomes of the host cell induces conformational changes in the Spike glycoprotein (PubMed:32142651, PubMed:32075877, PubMed:32155444). Uses also human TMPRSS2 for priming in human lung cells which is an essential step for viral entry (PubMed:32142651). Proteolysis by cathepsin CTSL may unmask the fusion peptide of S2 and activate membranes fusion within endosomes.[HAMAP-Rule:MF_04099][29] [30] [31] mediates fusion of the virion and cellular membranes by acting as a class I viral fusion protein. Under the current model, the protein has at least three conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and target cell membrane fusion, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes.[HAMAP-Rule:MF_04099] Acts as a viral fusion peptide which is unmasked following S2 cleavage occurring upon virus endocytosis.[HAMAP-Rule:MF_04099]
Publication Abstract from PubMed
Within a year after its emergence, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 100 million people worldwide with a death toll over 2 million. Vaccination remains the best hope to ultimately put this pandemic to an end. Here, using Trimer-Tag technology, we produced both wild-type (WT) and furin site mutant (MT) S-Trimers for COVID-19 vaccine studies. Cryo-EM structures of the WT and MT S-Trimers, determined at 3.2 A and 2.6 A respectively, revealed that both antigens adopt a tightly closed conformation and their structures are essentially identical to that of the previously solved full-length WT S protein in detergent. The tightly closed conformation is stabilized by fatty acid and polysorbate 80 binding at the receptor binding domains (RBDs) and the N terminal domains (NTDs) respectively. Additionally, we identified an important pH switch in the WT S-Trimer that shows dramatic conformational change and accounts for its increased stability at lower pH. These results validate Trimer-Tag as a platform technology in production of metastable WT S-Trimer as a candidate for COVID-19 subunit vaccine.IMPORTANCEEffective vaccine against SARS-CoV-2 is critical to end the COVID-19 pandemic. Here, using Trimer-Tag technology, we are able to produce stable and large quantities of WT S-Trimer, a subunit vaccine candidate for COVID-19 with high safety and efficacy from animal and Phase 1 clinical trial studies. Cryo-EM structures of the S-Trimer subunit vaccine candidate show that it predominately adopts tightly closed pre-fusion state, and resembles that of the native and full-length spike in detergent, confirming its structural integrity. WT S-Trimer is currently being evaluated in global Phase 2/3 clinical trial. Combining with published structures of the S protein, we also propose a model to dissect the conformation change of the spike protein before receptor binding.
Cryo-EM structure of S-Trimer, a subunit vaccine candidate for COVID-19.,Ma J, Su D, Sun Y, Huang X, Liang Y, Fang L, Ma Y, Li W, Liang P, Zheng S J Virol. 2021 Mar 10. pii: JVI.00194-21. doi: 10.1128/JVI.00194-21. PMID:33692215[32]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Simon MP, Pedeutour F, Sirvent N, Grosgeorge J, Minoletti F, Coindre JM, Terrier-Lacombe MJ, Mandahl N, Craver RD, Blin N, Sozzi G, Turc-Carel C, O'Brien KP, Kedra D, Fransson I, Guilbaud C, Dumanski JP. Deregulation of the platelet-derived growth factor B-chain gene via fusion with collagen gene COL1A1 in dermatofibrosarcoma protuberans and giant-cell fibroblastoma. Nat Genet. 1997 Jan;15(1):95-8. PMID:8988177 doi:10.1038/ng0197-95
- ↑ Sandberg AA, Anderson WD, Fredenberg C, Hashimoto H. Dermatofibrosarcoma protuberans of breast. Cancer Genet Cytogenet. 2003 Apr 1;142(1):56-9. PMID:12660034
- ↑ Gensure RC, Makitie O, Barclay C, Chan C, Depalma SR, Bastepe M, Abuzahra H, Couper R, Mundlos S, Sillence D, Ala Kokko L, Seidman JG, Cole WG, Juppner H. A novel COL1A1 mutation in infantile cortical hyperostosis (Caffey disease) expands the spectrum of collagen-related disorders. J Clin Invest. 2005 May;115(5):1250-7. PMID:15864348 doi:10.1172/JCI22760
- ↑ Simon MP, Pedeutour F, Sirvent N, Grosgeorge J, Minoletti F, Coindre JM, Terrier-Lacombe MJ, Mandahl N, Craver RD, Blin N, Sozzi G, Turc-Carel C, O'Brien KP, Kedra D, Fransson I, Guilbaud C, Dumanski JP. Deregulation of the platelet-derived growth factor B-chain gene via fusion with collagen gene COL1A1 in dermatofibrosarcoma protuberans and giant-cell fibroblastoma. Nat Genet. 1997 Jan;15(1):95-8. PMID:8988177 doi:10.1038/ng0197-95
- ↑ Sandberg AA, Anderson WD, Fredenberg C, Hashimoto H. Dermatofibrosarcoma protuberans of breast. Cancer Genet Cytogenet. 2003 Apr 1;142(1):56-9. PMID:12660034
- ↑ Nuytinck L, Freund M, Lagae L, Pierard GE, Hermanns-Le T, De Paepe A. Classical Ehlers-Danlos syndrome caused by a mutation in type I collagen. Am J Hum Genet. 2000 Apr;66(4):1398-402. Epub 2000 Mar 17. PMID:10739762 doi:S0002-9297(07)60165-7
- ↑ Malfait F, Symoens S, De Backer J, Hermanns-Le T, Sakalihasan N, Lapiere CM, Coucke P, De Paepe A. Three arginine to cysteine substitutions in the pro-alpha (I)-collagen chain cause Ehlers-Danlos syndrome with a propensity to arterial rupture in early adulthood. Hum Mutat. 2007 Apr;28(4):387-95. PMID:17211858 doi:10.1002/humu.20455
- ↑ Simon MP, Pedeutour F, Sirvent N, Grosgeorge J, Minoletti F, Coindre JM, Terrier-Lacombe MJ, Mandahl N, Craver RD, Blin N, Sozzi G, Turc-Carel C, O'Brien KP, Kedra D, Fransson I, Guilbaud C, Dumanski JP. Deregulation of the platelet-derived growth factor B-chain gene via fusion with collagen gene COL1A1 in dermatofibrosarcoma protuberans and giant-cell fibroblastoma. Nat Genet. 1997 Jan;15(1):95-8. PMID:8988177 doi:10.1038/ng0197-95
- ↑ Sandberg AA, Anderson WD, Fredenberg C, Hashimoto H. Dermatofibrosarcoma protuberans of breast. Cancer Genet Cytogenet. 2003 Apr 1;142(1):56-9. PMID:12660034
- ↑ Simon MP, Pedeutour F, Sirvent N, Grosgeorge J, Minoletti F, Coindre JM, Terrier-Lacombe MJ, Mandahl N, Craver RD, Blin N, Sozzi G, Turc-Carel C, O'Brien KP, Kedra D, Fransson I, Guilbaud C, Dumanski JP. Deregulation of the platelet-derived growth factor B-chain gene via fusion with collagen gene COL1A1 in dermatofibrosarcoma protuberans and giant-cell fibroblastoma. Nat Genet. 1997 Jan;15(1):95-8. PMID:8988177 doi:10.1038/ng0197-95
- ↑ Sandberg AA, Anderson WD, Fredenberg C, Hashimoto H. Dermatofibrosarcoma protuberans of breast. Cancer Genet Cytogenet. 2003 Apr 1;142(1):56-9. PMID:12660034
- ↑ Labhard ME, Wirtz MK, Pope FM, Nicholls AC, Hollister DW. A cysteine for glycine substitution at position 1017 in an alpha 1(I) chain of type I collagen in a patient with mild dominantly inherited osteogenesis imperfecta. Mol Biol Med. 1988 Dec;5(3):197-207. PMID:3244312
- ↑ Starman BJ, Eyre D, Charbonneau H, Harrylock M, Weis MA, Weiss L, Graham JM Jr, Byers PH. Osteogenesis imperfecta. The position of substitution for glycine by cysteine in the triple helical domain of the pro alpha 1(I) chains of type I collagen determines the clinical phenotype. J Clin Invest. 1989 Oct;84(4):1206-14. PMID:2794057 doi:http://dx.doi.org/10.1172/JCI114286
- ↑ Deak SB, Scholz PM, Amenta PS, Constantinou CD, Levi-Minzi SA, Gonzalez-Lavin L, Mackenzie JW. The substitution of arginine for glycine 85 of the alpha 1(I) procollagen chain results in mild osteogenesis imperfecta. The mutation provides direct evidence for three discrete domains of cooperative melting of intact type I collagen. J Biol Chem. 1991 Nov 15;266(32):21827-32. PMID:1718984
- ↑ Mottes M, Sangalli A, Valli M, Gomez Lira M, Tenni R, Buttitta P, Pignatti PF, Cetta G. Mild dominant osteogenesis imperfecta with intrafamilial variability: the cause is a serine for glycine alpha 1(I) 901 substitution in a type-I collagen gene. Hum Genet. 1992 Jul;89(5):480-4. PMID:1634225
- ↑ Shapiro JR, Stover ML, Burn VE, McKinstry MB, Burshell AL, Chipman SD, Rowe DW. An osteopenic nonfracture syndrome with features of mild osteogenesis imperfecta associated with the substitution of a cysteine for glycine at triple helix position 43 in the pro alpha 1(I) chain of type I collagen. J Clin Invest. 1992 Feb;89(2):567-73. PMID:1737847 doi:http://dx.doi.org/10.1172/JCI115622
- ↑ Valli M, Zolezzi F, Mottes M, Antoniazzi F, Stanzial F, Tenni R, Pignatti P, Cetta G. Gly85 to Val substitution in pro alpha 1(I) chain causes mild osteogenesis imperfecta and introduces a susceptibility to protease digestion. Eur J Biochem. 1993 Oct 1;217(1):77-82. PMID:8223589
- ↑ Lee KS, Song HR, Cho TJ, Kim HJ, Lee TM, Jin HS, Park HY, Kang S, Jung SC, Koo SK. Mutational spectrum of type I collagen genes in Korean patients with osteogenesis imperfecta. Hum Mutat. 2006 Jun;27(6):599. PMID:16705691 doi:10.1002/humu.9423
- ↑ Pollitt R, McMahon R, Nunn J, Bamford R, Afifi A, Bishop N, Dalton A. Mutation analysis of COL1A1 and COL1A2 in patients diagnosed with osteogenesis imperfecta type I-IV. Hum Mutat. 2006 Jul;27(7):716. PMID:16786509 doi:10.1002/humu.9430
- ↑ Wang Z, Xu DL, Chen Z, Hu JY, Yang Z, Wang LT. [A new mutation in COL1A1 gene in a family with osteogenesis imperfecta]. Zhonghua Yi Xue Za Zhi. 2006 Jan 17;86(3):170-3. PMID:16638323
- ↑ Kataoka K, Ogura E, Hasegawa K, Inoue M, Seino Y, Morishima T, Tanaka H. Mutations in type I collagen genes in Japanese osteogenesis imperfecta patients. Pediatr Int. 2007 Oct;49(5):564-9. PMID:17875077 doi:10.1111/j.1442-200X.2007.02422.x
- ↑ Witecka J, Augusciak-Duma AM, Kruczek A, Szydlo A, Lesiak M, Krzak M, Pietrzyk JJ, Mannikko M, Sieron AL. Two novel COL1A1 mutations in patients with osteogenesis imperfecta (OI) affect the stability of the collagen type I triple-helix. J Appl Genet. 2008;49(3):283-95. doi: 10.1007/BF03195625. PMID:18670065 doi:10.1007/BF03195625
- ↑ Simon MP, Pedeutour F, Sirvent N, Grosgeorge J, Minoletti F, Coindre JM, Terrier-Lacombe MJ, Mandahl N, Craver RD, Blin N, Sozzi G, Turc-Carel C, O'Brien KP, Kedra D, Fransson I, Guilbaud C, Dumanski JP. Deregulation of the platelet-derived growth factor B-chain gene via fusion with collagen gene COL1A1 in dermatofibrosarcoma protuberans and giant-cell fibroblastoma. Nat Genet. 1997 Jan;15(1):95-8. PMID:8988177 doi:10.1038/ng0197-95
- ↑ Sandberg AA, Anderson WD, Fredenberg C, Hashimoto H. Dermatofibrosarcoma protuberans of breast. Cancer Genet Cytogenet. 2003 Apr 1;142(1):56-9. PMID:12660034
- ↑ Grant SF, Reid DM, Blake G, Herd R, Fogelman I, Ralston SH. Reduced bone density and osteoporosis associated with a polymorphic Sp1 binding site in the collagen type I alpha 1 gene. Nat Genet. 1996 Oct;14(2):203-5. PMID:8841196 doi:10.1038/ng1096-203
- ↑ Uitterlinden AG, Burger H, Huang Q, Yue F, McGuigan FE, Grant SF, Hofman A, van Leeuwen JP, Pols HA, Ralston SH. Relation of alleles of the collagen type Ialpha1 gene to bone density and the risk of osteoporotic fractures in postmenopausal women. N Engl J Med. 1998 Apr 9;338(15):1016-21. PMID:9535665
- ↑ Simon MP, Pedeutour F, Sirvent N, Grosgeorge J, Minoletti F, Coindre JM, Terrier-Lacombe MJ, Mandahl N, Craver RD, Blin N, Sozzi G, Turc-Carel C, O'Brien KP, Kedra D, Fransson I, Guilbaud C, Dumanski JP. Deregulation of the platelet-derived growth factor B-chain gene via fusion with collagen gene COL1A1 in dermatofibrosarcoma protuberans and giant-cell fibroblastoma. Nat Genet. 1997 Jan;15(1):95-8. PMID:8988177 doi:10.1038/ng0197-95
- ↑ Sandberg AA, Anderson WD, Fredenberg C, Hashimoto H. Dermatofibrosarcoma protuberans of breast. Cancer Genet Cytogenet. 2003 Apr 1;142(1):56-9. PMID:12660034
- ↑ Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O, Graham BS, McLellan JS. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020 Feb 19. pii: science.abb2507. doi: 10.1126/science.abb2507. PMID:32075877 doi:http://dx.doi.org/10.1126/science.abb2507
- ↑ Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Muller MA, Drosten C, Pohlmann S. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020 Apr 16;181(2):271-280.e8. doi: 10.1016/j.cell.2020.02.052. Epub 2020, Mar 5. PMID:32142651 doi:http://dx.doi.org/10.1016/j.cell.2020.02.052
- ↑ Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell. 2020 Mar 6. pii: S0092-8674(20)30262-2. doi: 10.1016/j.cell.2020.02.058. PMID:32155444 doi:http://dx.doi.org/10.1016/j.cell.2020.02.058
- ↑ Ma J, Su D, Sun Y, Huang X, Liang Y, Fang L, Ma Y, Li W, Liang P, Zheng S. Cryo-EM structure of S-Trimer, a subunit vaccine candidate for COVID-19. J Virol. 2021 Mar 10. pii: JVI.00194-21. doi: 10.1128/JVI.00194-21. PMID:33692215 doi:http://dx.doi.org/10.1128/JVI.00194-21
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