CFH and Macular Degeneration
This web page was produced as an assignment for Gen677 at UW-Madison Spring 2010.
CFH
CFH
Protein Sequence
Below is the protein sequence for CFH. CFH is 1,321 amino acids long. It's accession number is NP_000177.
MRLLAKIICLMLWAICVAEDCNELPPRRNTEILTGSWSDQTYPE
GTQAIYKCRPGYRSLGNVIMVCRKGEWVALNPLRKCQKRPCGHPGDTPFGTFTLTGGN
VFEYGVKAVYTCNEGYQLLGEINYRECDTDGWTNDIPICEVVKCLPVTAPENGKIVSS
AMEPDREYHFGQAVRFVCNSGYKIEGDEEMHCSDDGFWSKEKPKCVEISCKSPDVING
SPISQKIIYKENERFQYKCNMGYEYSERGDAVCTESGWRPLPSCEEKSCDNPYIPNGD
YSPLRIKHRTGDEITYQCRNGFYPATRGNTAKCTSTGWIPAPRCTLKPCDYPDIKHGG
LYHENMRRPYFPVAVGKYYSYYCDEHFETPSGSYWDHIHCTQDGWSPAVPCLRKCYFP
YLENGYNQNHGRKFVQGKSIDVACHPGYALPKAQTTVTCMENGWSPTPRCIRVKTCSK
SSIDIENGFISESQYTYALKEKAKYQCKLGYVTADGETSGSITCGKDGWSAQPTCIKS
CDIPVFMNARTKNDFTWFKLNDTLDYECHDGYESNTGSTTGSIVCGYNGWSDLPICYE
RECELPKIDVHLVPDRKKDQYKVGEVLKFSCKPGFTIVGPNSVQCYHFGLSPDLPICK
EQVQSCGPPPELLNGNVKEKTKEEYGHSEVVEYYCNPRFLMKGPNKIQCVDGEWTTLP
VCIVEESTCGDIPELEHGWAQLSSPPYYYGDSVEFNCSESFTMIGHRSITCIHGVWTQ
LPQCVAIDKLKKCKSSNLIILEEHLKNKKEFDHNSNIRYRCRGKEGWIHTVCINGRWD
PEVNCSMAQIQLCPPPPQIPNSHNMTTTLNYRDGEKVSVLCQENYLIQEGEEITCKDG
RWQSIPLCVEKIPCSQPPQIEHGTINSSRSSQESYAHGTKLSYTCEGGFRISEENETT
CYMGKWSSPPQCEGLPCKSPPEISHGVVAHMSDSYQYGEEVTYKCFEGFGIDGPAIAK
CLGEKWSHPPSCIKTDCLSLPSFENAIPMGEKKDVYKAGEQVTYTCATYYKMDGASNV
TCINSRWTGRPTCRDTSCVNPPTVQNAYIVSRQMSKYPSGERVRYQCRSPYEMFGDEE
VMCLNGNWTEPPQCKDSTGKCGPPPPIDNGDITSFPLSVYAPASSVEYQCQNLYQLEG
NKRITCRNGQWSEPPKCLHPCVISREIMENYNIALRWTAKQKLYSRTGESVEFVCKRG
YRLSSRSHTLRTTCWDGKLEYPTCAKR
MRLLAKIICLMLWAICVAEDCNELPPRRNTEILTGSWSDQTYPE
GTQAIYKCRPGYRSLGNVIMVCRKGEWVALNPLRKCQKRPCGHPGDTPFGTFTLTGGN
VFEYGVKAVYTCNEGYQLLGEINYRECDTDGWTNDIPICEVVKCLPVTAPENGKIVSS
AMEPDREYHFGQAVRFVCNSGYKIEGDEEMHCSDDGFWSKEKPKCVEISCKSPDVING
SPISQKIIYKENERFQYKCNMGYEYSERGDAVCTESGWRPLPSCEEKSCDNPYIPNGD
YSPLRIKHRTGDEITYQCRNGFYPATRGNTAKCTSTGWIPAPRCTLKPCDYPDIKHGG
LYHENMRRPYFPVAVGKYYSYYCDEHFETPSGSYWDHIHCTQDGWSPAVPCLRKCYFP
YLENGYNQNHGRKFVQGKSIDVACHPGYALPKAQTTVTCMENGWSPTPRCIRVKTCSK
SSIDIENGFISESQYTYALKEKAKYQCKLGYVTADGETSGSITCGKDGWSAQPTCIKS
CDIPVFMNARTKNDFTWFKLNDTLDYECHDGYESNTGSTTGSIVCGYNGWSDLPICYE
RECELPKIDVHLVPDRKKDQYKVGEVLKFSCKPGFTIVGPNSVQCYHFGLSPDLPICK
EQVQSCGPPPELLNGNVKEKTKEEYGHSEVVEYYCNPRFLMKGPNKIQCVDGEWTTLP
VCIVEESTCGDIPELEHGWAQLSSPPYYYGDSVEFNCSESFTMIGHRSITCIHGVWTQ
LPQCVAIDKLKKCKSSNLIILEEHLKNKKEFDHNSNIRYRCRGKEGWIHTVCINGRWD
PEVNCSMAQIQLCPPPPQIPNSHNMTTTLNYRDGEKVSVLCQENYLIQEGEEITCKDG
RWQSIPLCVEKIPCSQPPQIEHGTINSSRSSQESYAHGTKLSYTCEGGFRISEENETT
CYMGKWSSPPQCEGLPCKSPPEISHGVVAHMSDSYQYGEEVTYKCFEGFGIDGPAIAK
CLGEKWSHPPSCIKTDCLSLPSFENAIPMGEKKDVYKAGEQVTYTCATYYKMDGASNV
TCINSRWTGRPTCRDTSCVNPPTVQNAYIVSRQMSKYPSGERVRYQCRSPYEMFGDEE
VMCLNGNWTEPPQCKDSTGKCGPPPPIDNGDITSFPLSVYAPASSVEYQCQNLYQLEG
NKRITCRNGQWSEPPKCLHPCVISREIMENYNIALRWTAKQKLYSRTGESVEFVCKRG
YRLSSRSHTLRTTCWDGKLEYPTCAKR
Amino acid variance at position 402 among species
When the protein sequences of CFH of dog, mouse, chicken, rat, and cattle were compared to that of human CFH, there was great variance at position 402 (the location for the polymorphism that increases risk of AMD). Only chimpanzees share the same amino acid, tyrosine, at position 402. Despite this lack of conservation, none of these other animals seem to normally have AMD.
Further examination of the nature of the different amino acids at position 402 in the different species has not revealed a pattern of the necessary amino acid to increase the risk of AMD. The variances at position 402 for the different species are:
Further examination of the nature of the different amino acids at position 402 in the different species has not revealed a pattern of the necessary amino acid to increase the risk of AMD. The variances at position 402 for the different species are:
- asparagine (N) in dog
- glutamic acid (E) in cattle
- proline (P) in mouse
- tryptophan (W) in rat
- methionine (M) in chicken
Motifs
CFH has repeated Sushi domains (represented as green ovals in the image below). The Sushi domain is also known as the Complement control protein (CCP) modules. They are commonly found in proteins involved in the Complement system. Other proteins that have sushi domains are involved in Hematopoietic cell lineage, Cell adhesion molecules, Cytokine-cytokine receptor interaction, Neuroactive ligand-receptor interaction, B cell receptor signaling pathway, Tyrosine metabolism, Methane metabolism
Sushi domains are typically ~60 amino acids long. It's structure is composed of a beta-sandwich arrangement. There are three beta-strands that are hydrogen-bonded together to form a triple-stranded region.Two different beta-strands form the other part of the arrangement.
Sushi domains are typically ~60 amino acids long. It's structure is composed of a beta-sandwich arrangement. There are three beta-strands that are hydrogen-bonded together to form a triple-stranded region.Two different beta-strands form the other part of the arrangement.
Below is motif sequence of the Sushi domain.
Sushi domains are green ovals (image taken from http://pfam.janelia.org/)
Sushi motif sequence (image taken from http://pfam.janelia.org/)
Below are two examples of the seventh module of Sushi. The example on the left is that of an individual at risk for AMD. The example on the right is that of an individual not at risk for AMD. The polymorphism found that changes a tyrosine to a histidine is within the seventh Sushi domain.
CFH of an individual at risk for AMD
CFH of an individual not at risk for AMD
Protein sequence taken from NCBI Entrez Protein: http://www.ncbi.nlm.nih.gov/protein
Motifs and domains taken from Pfam: http://pfam.janelia.org/
