COL1A1

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Type I collagen, alpha 1
Type I collagen, alpha 1
according to PDB  3HR2
other names
  • Alpha-1 Type I Collagen
  • Collagen alpha-1 (I) chain
  • Type I collagen alpha 1 chain

Available structural data : 3HQV , 1Q7D , 3EJH , 3GXE

Properties of human protein
Mass / length primary structure 162,504 daltons / 1,464 amino acids (isoform 1)

155,178 daltons / 1,398 amino acids (isoform 2)

152,514 daltons / 1,374 amino acids (isoform 3)

128,538 daltons / 1,158 amino acids (isoform 4)

Isoforms 4th
Identifier
Gene names COL1A1 EDSC, OI1, OI2, OI3, OI4
External IDs
Occurrence
Parent taxon Bilateria
Orthologue
human House mouse
Entrez 1277 12842
Ensemble ENSG00000108821 ENSMUSG00000001506
UniProt P02452 P11087
Refseq (mRNA) NM_000088 NM_007742
Refseq (protein) NP_000079 NP_031768
Gene locus Chr 17: 50.18 - 50.2 Mb Chr 11: 94.94 - 94.95 Mb
PubMed search 1277 12842

Type I collagen, alpha 1 , also known as alpha-1 type I collagen , is a protein that is encoded by the COL1A1 gene in the human organism . In mammals, collagen type I, a fibrillar collagen , is the most common type of collagen and occurs in skin , tendons , fascia , bones , connective tissue , cartilage , vessels , internal organs, sclera and dentin .

Gene structure

The type I collagen α1 chain gene consists of 50 exons , over half of which are 54 base pairs (bp) in length or two to three times that length. They code for the sequence (GXY) 6 or a multiple thereof. COL1A1 is located on the long chromosome arm (q arm) between chromosome bands 17q21.3 and 17q22.1 of chromosome 17 . The gene locus ranges from 50.18 to 50.2 Mb.

function

Type I collagen has a triple helix as a tertiary structure . It contains two Pro-α1 (I) polypeptide chains , which are encoded by the gene described here, and one Pro-α2 (I) chain, which is encoded by the COL1A2 gene, in order to be able to produce a type I procollagen. This must procollagen outside the cell processed are. The subsequent cross-linking results in a very strong and mature collagen fibril type I. Mutations in this gene are associated with the hereditary disease osteogenesis imperfecta types I-IV, Ehlers-Danlos syndrome type VIIA, infantile cortical hyperostosis and idiopathic juvenile osteoporosis . Reciprocal translocations between the chromosomes 17 and 22 where the gene for a to Platelet-derived growth factor (PDGF) is to be, with a particulate type of skin tumor, which Dermatofibrosarcoma protuberans is mentioned that by the irregular expression of the growth factor associated may arise . Furthermore, the gene is localized in the extracellular space and in the nucleus , less often in the cytoskeleton , lysosome and cell membrane .

Interaction with other proteins

COL1A1 interacts with a total of 27 proteins:

Clinical Significance

Mutations in the COL1A1 gene could cause the following diseases:

  • Ehlers-Danlos syndrome, arthrochalasia type: In this syndrome, a mutation can be detected in the first 90 monomers in the helical region of the α1 (I) collagen. This syndrome has been studied in vitro and pericellular. It has been proven that this mutation prevents or delays the cleavage of the procollagen type IN propeptide (PINP) by the enzyme ADAMTS2 (procollagen type IN proteinase). The procollagen mutates to α1 (III) -pN collagen and is effectively integrated into the extracellular matrix by fibroblasts and osteoblasts . The diameter of dermal collagen fibrils is decimated dramatically and it favors the integration of α1 (III) -pN collagen in fibrils in vivo . The procollagen separates the protein domain , which had a high thermal stability, in the first 90 monomers at the N terminus of collagen type I and modifies the secondary structure of the adjacent enzyme ADAMTS2. Accordingly, this mutation is responsible for the fragility of the bones, thin skin, hip dislocation and a pronounced overmobility of the joints.
  • Ehlers-Danlos syndrome, classic type: The mutation is caused by the substitution of the amino acid cysteine with arginine at position 134 of the α1-strand type I collagen (the mutation can also be referred to as Arg134Cys). The arginine residue is highly conserved and is located in the X position of the Gly-XY triplet . As a consequence, intermolecular disulfide bridges are formed , which lead to collagen type I aggregation , which are retained in the cells. The modified protein interacts abnormally with other collagen-forming proteins and the structures of the type I collagen fibrils are destroyed. Researchers suggest that this collagen destruction causes certain signs and symptoms of this syndrome.
  • Osteogenesis imperfecta type I (OI1): Osteogenesis imperfecta is the most common hereditary disease caused by the COL1A1 gene . This hereditary disease is caused by a point mutation , more precisely by a transition . A G - A transition takes place at the first position of the 5 ' splice site of the intron at position 26, which is taken up by the mature mRNA. This reduces the performance of the mRNA, which leads to a decreased production of pro-alpha-1 (I) chains during translation in the fibroblasts. The synthesis of collagen is reduced. It usually leads to minimal bone deformation and reduced muscle strength.
  • Osteogenesis imperfecta type II (OI2): In this type, the fibroblasts produce two different pro-alpha-1 (I) chains. One chain is normal, the other chain is identified as cyanogen bromide peptide alpha-1 (I) CB6 , which contains the amino acid cysteine at the C terminus . This mutated chain underwent post-translational modification , which led to increased lysyl hydroxylation and hydroxylysyl glycosylation . This hinders the correct “twisting” of the triple collagen helix, which leads to a loss of stability. The reason for the mutation is a point mutation, more precisely a transversion . The amino acid glycine has been substituted for cysteine . Because of this substitution, the synthesis of collagen is reduced.
  • Osteogenesis imperfecta type III (OI3): The cause of this type is also a point mutation, more precisely a transversion. Glycine has been substituted for cysteine ​​at position 526 of the pro-alpha-1 (I) chain, which leads to an inhibition of the interaction between essential protein chains. The collagen type I production is also inhibited due to the inability of the procollagen strand to form a triple helix, which has a negative effect on the tissue.
  • Osteogenesis imperfecta type IV (OI4): This type is due to a point mutation, more precisely to a transition. Similar to OI2, the fibroblast produces two different pro-alpha-1 (I) chains. One is normal, while the other chain is identified as cyanogen bromide peptide alpha-1 (I) CB6 . The cause is a substitution of guanine with alanine , which led to a substitution of glycine for serine at position 832. All of this hinders the formation of a mature triple helix molecule and prevents the production of type I collagen.
  • Osteogenesis imperfecta in animals: Mutations in this gene have also been described as the cause of osteogenesis imperfecta (glass bone disease) in the dog breeds Retriever and Beagle .
  • Infantile cortical hyperostosis: This limited disease is caused by an Arg836Cys mutation in the COL1A1 gene. Subsequently, the fibroblasts produce abnormal α1 (I) dimeric chains that affect alpha-1 type I collagen and lead to heterozygosity . The dermal collagen fibrils are longer, more variable in shape and size and have a lower density.

Animal model

In order to generate an animal model for the sporadic lethal variant of osteogenesis imperfecta, which is caused by an in-frame deletion, transgenic mice with a deletion of the human gene were generated. A mouse line with moderate expression had a lethal phenotype with an extensive fracture at birth in approximately 6% of the transgenic mice , while the fracture was non-lethal in 33%. The remaining 61% of the transgenic mice had no apparent fractures. In another animal model, mice with a specific mutation in the COL1A1 gene exhibited ocular hypertension (intraocular hypertension) because the protein COL1A1 is no longer recognized as a substrate by a collagenase . Researchers suspect an association between intraocular pressure and the movement of collagen fibrils.

Individual evidence

  1. ↑ a b COL1A1.  In: Online Mendelian Inheritance in Man . (English)
  2. ↑ COL1A1 collagen, type I, alpha 1 (human)
  3. ↑ a b COL1A1. In: GeneCards (English).
  4. ↑ Wayne A. Cabral, Elena Makareeva: Mutations Near Amino End of α1 (I) Collagen Cause Combined Osteogenesis Imperfecta / Ehlers-Danlos Syndrome by Interference with N-propeptide Processing . In: The Journal of Biological Chemistry (jbc) . February 22, 2005. doi : 10.1074 / jbc.M414698200 .
  5. ^ Lieve Nuytinck, Margarida Freund: Classical Ehlers-Danlos Syndrome Caused by a Mutation in Type I Collagen . In: The American Journal of Human Genetics (AJHG) . March 17, 2000, pp. 1398-1402. doi : 10.1086 / 302859 . PMID 10739762 . PMC 1288203 (free full text).
  6. ↑ DW Rowe, JR Shapiro: Diminished type I collagen synthesis and reduced alpha 1 (I) collagen messenger RNA in cultured fibroblasts from patients with dominantly inherited (type I) osteogenesis imperfecta. . In: The Journal of Clinical Investigation (JCI) . Aug 1, 1985, pp. 604-611.
  7. ↑ Beat U. Steinmann, George R. Martin: Synthesis and degradation of collagen by skin fibroblasts from controls and from patients with osteogenesis imperfecta . In: FEBS Letters . 101, No. 2, May 15, 1979, pp. 269-272. doi : 10.1016 / 0014-5793 (79) 81023-6 .  ( Page no longer available , search in web archives )  Info: The link was automatically marked as defective. Please check the link according to the instructions and then remove this notice.@1@ 2Template: Dead Link / www.febsletters.org  
  8. ^ BJ Starman, D. Eyre: 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. . In: The Journal of Clinical Investigation (JCI) . October 1, 1989, pp. 1206-1214.
  9. ^ Joan C. Marini, Dorothy K. Grange: Detection of a point mutation in one alpha-1 (I) collagen allele (COL1A1) by RNA / RNA hybrid analysis. . (PDF; 7.49 MB) In: The Journal of Biological Chemistry (jbc) . 264, No. 20, July 15, 1989, pp. 11893-11900.
  10. ↑ Ekkehard Schütz et al.: Osteogenesis imperfecta in the dachshund. In: Small Animal Practice. 57 (2012), pp. 57-62.
  11. ↑ Struan FA Grant, David M. Reid: Reduced bone density and osteoporosis associated with a polymorphic Sp1 binding site in the collagen type I alpha 1 gene. . In: Nature Genetics . 1996, pp. 203-205. doi : 10.1038 / ng1096-203 . PMID 8841196 .
  12. ↑ Robert C. Gensure, Outi Mäkitie: A novel COL1A1 mutation in infantile cortical hyperostosis (Caffey disease) Expands the spectrum of collagen-related disorders. . In: The Journal of Biological Chemistry (jbc) . 115, May 2, 2005.
  13. ↑ R. Pereira, JS Khillan: Transgenic mice expressing a Partially deleted genes for type I procollagen (COL1A1). A breeding line with a phenotype of spontaneous fractures and decreased bone collagen and mineral. . In: The Journal of Clinical Investigation (JCI) . February 1, 1993. doi : 10.1172 / JCI116252 .