CRMP1
Komplementni faktor I, znan i kao inaktivator C3b/C4b, jest protein /enzim koji je kod ljudi kodiran genom CFI sa hromosoma 4. To je protein komplementnog sistema, prvi put izoliran 1966. iz zamorčevog seruma,[5] koji regulira aktivaciju komplementa cijepanjem ćelijske ili fluidne faze C3b i C4b.[6] To je rastvorljivi glikoprotein koji cirkulira ljudskom krvlju, u prosječnoj koncentraciji od 35μg/mL.[7]
Aminokiselinska sekvenca
urediDužina polipeptidnog lanca je 583 aminokiselina, а molekulska težina 65.750 Da.[8]
10 | 20 | 30 | 40 | 50 | ||||
---|---|---|---|---|---|---|---|---|
MKLLHVFLLF | LCFHLRFCKV | TYTSQEDLVE | KKCLAKKYTH | LSCDKVFCQP | ||||
WQRCIEGTCV | CKLPYQCPKN | GTAVCATNRR | SFPTYCQQKS | LECLHPGTKF | ||||
LNNGTCTAEG | KFSVSLKHGN | TDSEGIVEVK | LVDQDKTMFI | CKSSWSMREA | ||||
NVACLDLGFQ | QGADTQRRFK | LSDLSINSTE | CLHVHCRGLE | TSLAECTFTK | ||||
RRTMGYQDFA | DVVCYTQKAD | SPMDDFFQCV | NGKYISQMKA | CDGINDCGDQ | ||||
SDELCCKACQ | GKGFHCKSGV | CIPSQYQCNG | EVDCITGEDE | VGCAGFASVT | ||||
QEETEILTAD | MDAERRRIKS | LLPKLSCGVK | NRMHIRRKRI | VGGKRAQLGD | ||||
LPWQVAIKDA | SGITCGGIYI | GGCWILTAAH | CLRASKTHRY | QIWTTVVDWI | ||||
HPDLKRIVIE | YVDRIIFHEN | YNAGTYQNDI | ALIEMKKDGN | KKDCELPRSI | ||||
PACVPWSPYL | FQPNDTCIVS | GWGREKDNER | VFSLQWGEVK | LISNCSKFYG | ||||
NRFYEKEMEC | AGTYDGSIDA | CKGDSGGPLV | CMDANNVTYV | WGVVSWGENC | ||||
GKPEFPGVYT | KVANYFDWIS | YHVGRPFISQ | YNV |
Sinteza
urediGen za faktor I kod ljudi se nalazi na hromosomu 4.[9] Faktor I sintetizira se najviše u jetri, ali iu monocitima, fibroblastima, keratinocitima i endotelnim ćelijama.[10][11][12] Kada se sintetizira, to je polipeptidni lanac od 66 kDa sa N-vezanim glikanima na šest pozicija.[13] Zatim, faktor I cijepa se pomoću furina, kako bi se dobio zreli protein faktora I, koji je disulfidno povezani dimer teškog (ostaci 19-335, 51 kD) i lahkog lanca (ostaci 340-583, 37 kD).[14] Aktivan je samo zreli protein.
Struktura
urediFaktor I je glikoproteinski heterodimer koji se sastoji od disulfidno vezanog teškog i lahkog lanca.[15]
Teški lanac faktora I ima četiri domena: domen FI membranskog napadajućeg kompleksa (FIMAC), CD5 i domen receptora lipoproteina niske gustine 1 i 2 (LDLr1 i LDLr2).[16] Ima inhibitornu ulogu u održavanju enzima neaktivnim sve dok se ne susretne sa kompleksom koji formiraju supstrat (ili C3b ili C4b) i kofaktor proteina (faktor H, C4b-vezujući protein, receptor komplementa 1 i proteinski kofaktor membrane).[17] Nakon vezivanja enzima za kompleks supstrat–kofaktor, interfejs teški–lahki lanac je prekinut, a enzim se aktivira alosterijom.[17] Domeni LDL-receptora sadrže po jedno mjesto vezanja kalcija.
Lahki lanac faktora I sadrži samo domen serin-proteaza. Ovaj domen sadrži katalitskku trijadu His-362, Asp-411 i Ser-507, koja je odgovorna za specifično cijepanje C3b i C4b.[16] Uobičajeni inhibitori proteaze ne inaktiviraju potpuno faktor I[18] ali to mogu učiniti ako je enzim prethodno inkubiran sa svojim supstratom: ovo podržava predloženo preuređenje molekula nakon vezivanja za supstrat.
I teški i lahki lanci nose Asn-vezane glikana, na tri različita glikozilacijska mjesta.
Kristalna struktura ljudskog faktora I je deponovana kaao PDB: 2XRC .
Klinički značaj
urediDisregulirana aktivnost faktora I ima kliničke implikacije. Gubitak funkcijskih mutacija u genu za faktor I komplementa dovodi do niskog nivoa faktora I što rezultira povećanom aktivnošću komplementa. Nedostatak faktora I zauzvrat dovodi do niskih nivoa komponente komplementa 3 (C3), faktora B, faktora H i properdina u krvi, zbog neregulirane aktivacije C3-konvertaza i niskog nivoa IgG, zbog gubitka proizvodnje iC3b i C3dg. Pored sljedećih bolesti, nizak faktor I je povezan s rekurentnim bakterijskim infekcijama kod djece.
- Starosno vezana degeneracija makule
Rezultati istraživanja sugeriraju da mutacije u genu CFI doprinose razvoju degeneracije makule povezane sa starenjem.[19] Smatra se da je ovaj doprinos posljedica disregulacije alternativnog puta, što dovodi do povećane upale u očima.[20]
- Sindrom netipske hemolitske uremije
Sindrom netipske hemolitske uremije izazvan je prekomjernom aktivacijom komplementa.[21] Oko 5-10% slučajeva sindroma čini heterozigotost mutacija u domenu gena serin-proteaze CFI.[21]
Reference
uredi- ^ a b c GRCh38: Ensembl release 89: ENSG00000205403 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000058952 - Ensembl, maj 2017
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- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Nelson RA, Jensen J, Gigli I, Tamura N (mart 1966). "Methods for the separation, purification and measurement of nine components of hemolytic complement in guinea-pig serum". Immunochemistry. 3 (2): 111–35. doi:10.1016/0019-2791(66)90292-8. PMID 5960883.
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- ^ "UniProt, P05156" (jezik: engleski). Pristupljeno 22. 10. 2021.
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- ^ Whaley K (mart 1980). "Biosynthesis of the complement components and the regulatory proteins of the alternative complement pathway by human peripheral blood monocytes". The Journal of Experimental Medicine. 151 (3): 501–16. doi:10.1084/jem.151.3.501. PMC 2185797. PMID 6444659.
- ^ Tsiftsoglou SA, Arnold JN, Roversi P, Crispin MD, Radcliffe C, Lea SM, Dwek RA, Rudd PM, Sim RB (novembar 2006). "Human complement factor I glycosylation: structural and functional characterisation of the N-linked oligosaccharides". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1764 (11): 1757–66. CiteSeerX 10.1.1.712.1764. doi:10.1016/j.bbapap.2006.09.007. PMID 17055788.
- ^ "FURIN furin, paired basic amino acid cleaving enzyme [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Pristupljeno 30. 3. 2018.
- ^ "CFI complement factor I [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Pristupljeno 27. 3. 2018.
- ^ a b Sanchez-Gallego JI, Groeneveld TW, Krentz S, Nilsson SC, Villoutreix BO, Blom AM (april 2012). "Analysis of binding sites on complement factor I using artificial N-linked glycosylation". The Journal of Biological Chemistry. 287 (17): 13572–83. doi:10.1074/jbc.M111.326298. PMC 3340171. PMID 22393059.
- ^ a b Roversi P, Johnson S, Caesar JJ, McLean F, Leath KJ, Tsiftsoglou SA, Morgan BP, Harris CL, Sim RB, Lea SM (august 2011). "Structural basis for complement factor I control and its disease-associated sequence polymorphisms". Proceedings of the National Academy of Sciences of the United States of America. 108 (31): 12839–44. doi:10.1073/pnas.1102167108. PMC 3150940. PMID 21768352.
- ^ Ekdahl KN, Nilsson UR, Nilsson B (juni 1990). "Inhibition of factor I by diisopropylfluorophosphate. Evidence of conformational changes in factor I induced by C3b and additional studies on the specificity of factor I". Journal of Immunology. 144 (11): 4269–74. PMID 2140392.
- ^ Wang Q, Zhao HS, Li L (18. 2. 2016). "Association between complement factor I gene polymorphisms and the risk of age-related macular degeneration: a Meta-analysis of literature". International Journal of Ophthalmology. 9 (2): 298–305. doi:10.18240/ijo.2016.02.23. PMC 4761747. PMID 26949655.
- ^ Tan PL, Garrett ME, Willer JR, Campochiaro PA, Campochiaro B, Zack DJ, Ashley-Koch AE, Katsanis N (mart 2017). "Systematic Functional Testing of Rare Variants: Contributions of CFI to Age-Related Macular Degeneration". Investigative Ophthalmology & Visual Science. 58 (3): 1570–1576. doi:10.1167/iovs.16-20867. PMC 6022411. PMID 28282489.
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Dopunska literatura
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External links
uredi- GeneReviews/NCBI/NIH/UW entry on Atypical Hemolytic-Uremic Syndrome
- OMIM entries on Atypical Hemolytic-Uremic Syndrome
- The MEROPS online database for peptidases and their inhibitors: S01.199[mrtav link]