Homologs
Below are all the isoforms of ZAP70 and also the homologues within other species.
Human [Homo Sapiens]
ZAP-70, a tyrosine protein kinase, is found as two isoforms in humans; ZAP-70 isoform 1 and ZAP-70 isoform 2. There are two other isoforms which were found in the duration of the Human Genome Project in 2001. These are believed to be elongated forms, where it seems that alternative methionine start sites were used compared to the current isoforms. Therefore they cannot be considered as functional isoforms but rather as more “primitive” data, which was not yet thoroughly researched.
Zebrafish [Danio Rerio]
Zebrafish also have an innate and adaptive immune system as humans do. T and B lymphocytes form part of their adaptive immune system as well. ZAP70 in Zebrafish is an ortholog of the human ZAP-70.The original domains found in the human isoform 1 are also found in this ortholog. However its function in the immune system of the fish is not distinct [8]. It has been shown to have a role in lymphangiogenesis, the formation of new lymphatic vessels and the migration of angioblasts as well [9].
FASTA
Accession: NP_001018425.1
>DR MTEPAADLPFFYGSISRSEAEEHLKLAGMGGGLFLLRQCLRSLGGYVLSMIWNLDFYHYSIEKQLNGTYC IAGGKPHCGPAELCEYYSKDPDGLVCTLRKPCLRSPETEIRKGVFDNLRDNMLREYVRHTWKLEGDAMEQ AIISQAPQLEKLIATTAHEKMPWFHGKIPRQEGERRLYSGSQPDGKFLVRERDEMGTFALSVTYGKTVYH YQILRDKSGKIAMPEGTKFDTVWQLVEYLKMKPDGLVTVLREPCVNQNNAAPAPANAPRRSRGNGYTPPP MVPKPMGAEGSRPSLPMDHDGFTSPYDDPNELKKKTLFIKRDKLMIDEVELGSGNFGCVKKGVFKMESKQ IDVAIKVLKNENEKSVRDEMMREAEIMHQLSDPFIVRMIGLCEAEALMLVMEMAPAGPLNKFLSGKKDQI TTENIVMLMHQVSMGMKYLEGRNFVHRDLAARNVLLVNQQYAKISDFGLSKALGADDNYYKARTGGKWPL KWYAPECIHFHKFSSKSDVWSFGITMWEAFSFGGKPYKKMKGPEVITYIEGGSRLDCPAACPEAMYELMK ECWTYKHEERLNFAKVEEKMRTFYYSIAKKIPDYLKTENGTPPK
BLAST
Query ID: lcl|29078
Query Length: 604
House Mouse [Mus musculus]
This 618 amino acids long protein tyrosine kinase (Flat file) has a similar function as its human counterpart. Murine ZAP-70 is also involved in binding and activating T-cell receptors [10]. The same conserved arrangement of two SH2 domains in tandem and the protein tyrosine kinase domain can be seen in this homolog. It also has a role in thymocyte development and is important for the differentiation of the latter into CD4+ or CD8+ cells [11].
FASTA
Accession: NP_033565.2
>MM MPDPAAHLPFFYGSISRAEAEEHLKLAGMADGLFLLRQCLRSLGGYVLSLVHDVRFHHFPIERQLNGTYA IAGGKAHCGPAELCQFYSQDPDGLPCNLRKPCNRPPGLEPQPGVFDCLRDAMVRDYVRQTWKLEGDALEQ AIISQAPQVEKLIATTAHERMPWYHSSLTREEAERKLYSGQQTDGKFLLRPRKEQGTYALSLVYGKTVYH YLISQDKAGKYCIPEGTKFDTLWQLVEYLKLKADGLIYRLKEVCPNSSASAAVAAPTLPAHPSTFTQPQR RVDTLNSDGYTPEPARLASSTDKPRPMPMDTSVYESPYSDPEELKDKKLFLKRENLLVADIELGCGNFGS VRQGVYRMRKKQIDVAIKVLKQGTEKADKDEMMREAQIMHQLDNPYIVRLIGVCQAEALMLVMEMAGGGP LHKFLLGKKEEIPVSNVAELLHQVAMGMKYLEEKNFVHRDLAARNVLLVNRHYAKISDFGLSKALGADDS YYTARSAGKWPLKWYAPECINFRKFSSRSDVWSYGVTMWEAFSYGQKPYKKMKGPEVLDFIKQGKRMECP PECPPEMYALMSDCWIYKWEDRPDFLTVEQRMRNYYYSLASRAEGPPQCEQVAEAACG
BLAST
Query ID: lcl|29663
Query Length: 618
Cattle [Bos Taurus]
The homologs of ZAP-70 found in cattle ( Flat file ), dogs (Flat file) and the African clawed frog (Flat file) have the same conserved domains, which are arranged in the same manner of human ZAP-70, with the exception of the homolog found in dogs. There is no current literature on the exact functions of these homologs in their respective organisms however in cattle and frogs the same pattern of two SH2 domains in tandem, a linker and a protein tyrosine kinase domain is conserved. Interestingly in dogs, the shortest homolog of 60 amino acids is found with only a conserved protein tyrosine kinase region. It has been shown that ZAP-70 expression is reduced in canine leukaemia compared to the high expression usually seen in CD8+ and CD4+ canine T cells [12].
FASTA
Accession: NP_001179946.1
>BT MPDPAAHLPFFYGSISRAEAEEHLKLAGMADGLFLLRQCLRSLGGYVLSLVHEVRFHHFPIERQLNGTYA IAGGKAHCGPAELCEFYSRDPDGLPCNLRKPCNRPSGLEPQPGVFDNLRDAMVRDYVRQTWKLEGEALEQ AIISQAPQVEKLIATTAHERMPWYHSSLTREEAERKLYSGSQTDGKFLLRPRKEPGTYALSLIYGKTVYH YLISQDKAGKYCIPEGTKFDTLWQLVEYLKLKADGLIYCLKEACPNSSASSGAAAPTLPAHPSTFTQPQR RIDTLNSDGYTPEPARLVSSEKPRTMPMDTSVYESPYSDPEELKNKKLFLKRENLLMADIELGCGNFGSV RQGVYRMRKKQIDVAIKVLKQSTEKADKDEMMREAQIMHQLDNPYIVRLIGVCQAEALMLVMEMAGGGPL HKFLVGKKEEIPVSNVAELLHQVSMGMKYLEEKNFVHRDLAARNVLLVNRHYAKISDFGLSKALGADDSY YTARSAGKWPLKWYAPECINFRKFSSRSDVWSYGVTMWEAFSYGQKPYKKMKGPEVMAFIEQGKRMECPP ECPPEMYKLMSDCWTYKWEDRPDFAAVEQRMRTYYYSLATKAEEPAACGNGVEAACP
BLAST
Query ID: lcl|46328
Query Length: 617
African Clawed Frog [Xenopus laevis]
The homologs of ZAP-70 found in cattle ( Flat file ), dogs (Flat file) and the African clawed frog (Flat file) have the same conserved domains, which are arranged in the same manner of human ZAP-70, with the exception of the homolog found in dogs. There is no current literature on the exact functions of these homologs in their respective organisms however in cattle and frogs the same pattern of two SH2 domains in tandem, a linker and a protein tyrosine kinase domain is conserved. Interestingly in dogs, the shortest homolog of 60 amino acids is found with only a conserved protein tyrosine kinase region. It has been shown that ZAP-70 expression is reduced in canine leukaemia compared to the high expression usually seen in CD8+ and CD4+ canine T cells [12].
FASTA
Accession: NP_001087005.1
>XL MPDVAGHLPFYYGSISRADAEEYLKLGGMMDGLFLLRQCLRTLGGYVLSMVYNVHFHHYPVERQLNGTYA IAGGKAHCGPAELCEYYSKDADGLSCTLRRPCNRPVGVECQAGVFDNMRDNMMREYVRQTWKLEGDALEQ AIISQAPQVEKLIATTAHERMAWYHGSISRDEAERKLYSGAQPDGKFLMRERKENGTYALSVMYGKTVYH YKIDQDKSGKYSIPEGTKFDTLWQLVEYLKLKSDGILAVLKESCANASTFSIAPAAAPPSLPKVRPVASN SDGYTPEPFLGKSRILPMDTSVYESPYSDPEELKERKLFVKRELLLIDEVELGSGNFGCVKKGVYKLKKR QIDVAIKVLKVQEEKNVRDEMMKEAEFMHQLDNPYIVRMIGVCEAENLMLVMEMASGGPLNKFLGAKKDT ITVSNVVELMHQVSMGMKYLEGKNFVHRDLAARNVLMVNQHYAKISDFGLSKALAADDSYYKAKSFGKWP LKWYAPECINYRKFSSRSDVWSYGITMWEAFSYGQKPYKKLKGTEVMSFIERNERLACPASCPPEMYQLM LDCWIFKMEDRPNFENVEYRMRMYYYSIADKPDKESKEGKEGKEAEAGAAAEAPGKE
BLAST
Query ID: lcl|3707
Query Length: 617
Dog [Canis lupus familiaris]
The homologs of ZAP-70 found in cattle ( Flat file ), dogs (Flat file) and the African clawed frog (Flat file) have the same conserved domains, which are arranged in the same manner of human ZAP-70, with the exception of the homolog found in dogs. There is no current literature on the exact functions of these homologs in their respective organisms however in cattle and frogs the same pattern of two SH2 domains in tandem, a linker and a protein tyrosine kinase domain is conserved. Interestingly in dogs, the shortest homolog of 60 amino acids is found with only a conserved protein tyrosine kinase region. It has been shown that ZAP-70 expression is reduced in canine leukaemia compared to the high expression usually seen in CD8+ and CD4+ canine T cells [12].
FASTA
Accession: ACJ38124.1
>CF NFRKFSSRSDVWSYGVTMWEAFSYGQKPYKKMKGPEVIAFIEQGKRMECPLECPPEMYTL
BLAST
Query ID: lcl|88211
Query Length: 60
Zeta-chain (TCR) associated protein kinase 70kDa, isoform CRA_a
This isoform of ZAP-70 was found as part of the Human Genome Project in 2001 [1]. It consists of 660 amino acids. From the N-terminus, the typical SH2 domains are found consecutively, the interdomain B region and to the C-terminus, the protein tyrosine kinase domain, all these features are found in this isoform.
FASTA
Accession: EAX01918.1
>HSa MSPGTPLLPTTAAYPPVPGNRLVSDKPACRSSADTRPSGQAWPTVGLRAAAGAFRTGSPLALGPETPQVA CLPGHPPVRPQVSGGPGAMPDPAAHLPFFYGSISRAEAEEHLKLAGMADGLFLLRQCLRSLGGYVLSLVH DVRFHHFPIERQLNGTYAIAGGKAHCGPAELCEFYSRDPDGLPCNLRKPCNRPSGLEPQPGVFDCLRDAM VRDYVRQTWKLEGEALEQAIISQAPQVEKLIATTAHERMPWYHSSLTREEAERKLYSGAQTDGKFLLRPR KEQGTYALSLIYGKTVYHYLISQDKAGKYCIPEGTKFDTLWQLVEYLKLKADGLIYCLKEACPNSSASNA SGAAAPTLPAHPSTLTHPQRRIDTLNSDGYTPEPARITSPDKPRPMPMDTSVYESPYSDPEELKDKKLFL KRDNLLIADIELGCGNFGSVRQGVYRMRKKQIDVAIKVLKQGTEKADTEEMMREAQIMHQLDNPYIVRLI GVCQAEALMLVMEMAGGGPLHKFLVGKREEIPVSNVAELLHQVSMGMKYLEEKNFVHRDLAARNVLLVNR HYAKISDFGLSKALGADDSYYTKMKGPEVMAFIEQGKRMECPPECPPELYALMSDCWIYKWEDRPDFLTV EQRMRACYYSLASKVEGPPGSTQKAEAACA
BLAST
Query ID: lcl|74780
Query Length: 660
Zeta-chain (TCR) associated protein kinase 70kDa, isoform CRA_b
Similarly this longer version of the above protein tyrosine kinase, consisting of 707 amino acids, was also recorded during the Human Genome Project in the database. Alternative methionine start sites seem to have been included when this sequence and that of isoform 1 are compared.
FASTA
Accession: EAX01919.1
>HSb MSPGTPLLPTTAAYPPVPGNRLVSDKPACRSSADTRPSGQAWPTVGLRAAAGAFRTGSPLALGPETPQVA CLPGHPPVRPQVSGGPGAMPDPAAHLPFFYGSISRAEAEEHLKLAGMADGLFLLRQCLRSLGGYVLSLVH DVRFHHFPIERQLNGTYAIAGGKAHCGPAELCEFYSRDPDGLPCNLRKPCNRPSGLEPQPGVFDCLRDAM VRDYVRQTWKLEGEALEQAIISQAPQVEKLIATTAHERMPWYHSSLTREEAERKLYSGAQTDGKFLLRPR KEQGTYALSLIYGKTVYHYLISQDKAGKYCIPEGTKFDTLWQLVEYLKLKADGLIYCLKEACPNSSASNA SGAAAPTLPAHPSTLTHPQRRIDTLNSDGYTPEPARITSPDKPRPMPMDTSVYESPYSDPEELKDKKLFL KRDNLLIADIELGCGNFGSVRQGVYRMRKKQIDVAIKVLKQGTEKADTEEMMREAQIMHQLDNPYIVRLI GVCQAEALMLVMEMAGGGPLHKFLVGKREEIPVSNVAELLHQVSMGMKYLEEKNFVHRDLAARNVLLVNR HYAKISDFGLSKALGADDSYYTARSAGKWPLKWYAPECINFRKFSSRSDVWSYGVTMWEALSYGQKPYKK MKGPEVMAFIEQGKRMECPPECPPELYALMSDCWIYKWEDRPDFLTVEQRMRACYYSLASKVEGPPGSTQ KAEAACA
BLAST
Query ID: lcl|28061
Query Length: 707
Tyrosine-protein kinase ZAP-70 isoform 1
Isoform 1, 619 amino acids in length, is the canonical sequence [2]. This means that it is the most predominantly seen isoform and that its length allows for a clear description of its various domains. ZAP-70 is an important molecule in the activation of T-cells or T lymphocytes cells which are important components of the adaptive immune system. T-cells are stimulated by processed peptide antigen on professional antigen presenting cells, which express Major Histocompatibility Complex Class II (MHC Class II). Once the T-cell receptor binds to the appropriate peptide antigen and MHC combination (roitts), a series of events is triggered downstream.
FASTA
Accession: NP_001070.2
>Hs1 MPDPAAHLPFFYGSISRAEAEEHLKLAGMADGLFLLRQCLRSLGGYVLSLVHDVRFHHFPIERQLNGTYA IAGGKAHCGPAELCEFYSRDPDGLPCNLRKPCNRPSGLEPQPGVFDCLRDAMVRDYVRQTWKLEGEALEQ AIISQAPQVEKLIATTAHERMPWYHSSLTREEAERKLYSGAQTDGKFLLRPRKEQGTYALSLIYGKTVYH YLISQDKAGKYCIPEGTKFDTLWQLVEYLKLKADGLIYCLKEACPNSSASNASGAAAPTLPAHPSTLTHP QRRIDTLNSDGYTPEPARITSPDKPRPMPMDTSVYESPYSDPEELKDKKLFLKRDNLLIADIELGCGNFG SVRQGVYRMRKKQIDVAIKVLKQGTEKADTEEMMREAQIMHQLDNPYIVRLIGVCQAEALMLVMEMAGGG PLHKFLVGKREEIPVSNVAELLHQVSMGMKYLEEKNFVHRDLAARNVLLVNRHYAKISDFGLSKALGADD SYYTARSAGKWPLKWYAPECINFRKFSSRSDVWSYGVTMWEALSYGQKPYKKMKGPEVMAFIEQGKRMEC PPECPPELYALMSDCWIYKWEDRPDFLTVEQRMRACYYSLASKVEGPPGSTQKAEAACA
BLAST
Query ID: lcl|31556
Query Length: 619
Tyrosine-protein kinase ZAP-70 isoform 2
Also known as Truncated Zeta Kinase or TZK ( Flat file ), this isoform has a small number of amino acids, 312, and lacks the two SH2 domains that are typical in the longer isoform 1. [7] The only domains that remain are the protein tyrosine kinase domain and two tyrosine residues from interdomain B. [7]
It does not take part in T-cell activation, as the two SH2 domains which are essential for the recruitment of ZAP-70 to the ITAMs of the zeta chain, previously phosphorylated by the Src family kinase, lck. While found along with ZAP-70 during the development of thymocytes, it is not present in significant numbers during the immune response where T-cells are activated [7]. Therefore the current hypothesis is that its function is that of a kinase in thymocytes and other cells. [7]
FASTA
Accession: NP_997402.1
>Hs2 MPMDTSVYESPYSDPEELKDKKLFLKRDNLLIADIELGCGNFGSVRQGVYRMRKKQIDVAIKVLKQGTEK ADTEEMMREAQIMHQLDNPYIVRLIGVCQAEALMLVMEMAGGGPLHKFLVGKREEIPVSNVAELLHQVSM GMKYLEEKNFVHRDLAARNVLLVNRHYAKISDFGLSKALGADDSYYTARSAGKWPLKWYAPECINFRKFS SRSDVWSYGVTMWEALSYGQKPYKKMKGPEVMAFIEQGKRMECPPECPPELYALMSDCWIYKWEDRPDFL TVEQRMRACYYSLASKVEGPPGSTQKAEAACA
BLAST
Query ID: lcl|84236
Query Length: 312
- NCBI: zeta-chain (TCR) associated protein kinase 70kDa, isoform CRA_a [Homo sapiens] , last accessed March 03, 2012
- P43403 (ZAP70_HUMAN) Reviewed in UniProtKB/Swiss-Prot , last modified February 22, 2012
- Delves, P. J., Martin, S. J., et al. Roitt's Essential Immunology. 12th Edition. USA: John Wiley & Sons; 2011.
- William E. Paul. Fundamental Immunology. 6th Edition. USA: Lippincott Williams &Wilkins;2008.
- Brdicka, T., Kadlecek, T.A., Roose, J.P., Pastuszak, A.W., Weiss, A. Intramolecular regulatory switch in ZAP-70: analogy with receptor tyrosine kinases. Mol. Cell. Biol. 2005; 25(12): 4924–4933.
- Kuroyama H., Ikeda T., Kasai M., Yamasaki S., Tatsumi M., Utsuyama M., Saito T., Hirokawa K. Identification of a novel isoform of ZAP-70, truncated ZAP kinase. Biochem. Biophys. Res. Commun. 2004; 315(4):935-941
- Deindl, S., Kadlecek , T. A., et al. Structural Basis for the Inhibition of Tyrosine Kinase Activity of ZAP-70. Cell. 2007; 129(4): 735-746.
- Øvergård, A.-C., Nerland, A. H., et al. Cloning, characterization, and expression pattern of Atlantic halibut (Hippoglossus hippoglossus L.) CD4-2, Lck, and ZAP70. Fish & Shellfish Immunology. 2010; 29(6): 987-997.
- Christie, T. L., Carter, A., et al. Syk and ZAP-70 function redundantly to promote angioblast migration. Developmental Biology. 2010; 340(1): 22-29.
- Gauen, L. K., Y. Zhu, et al. Interactions of p59fyn and ZAP-70 with T-cell receptor activation motifs: defining the nature of a signalling motif. Molecular and cellular biology. 1994; 14(6): 3729-3741.
- Wiest, D. L., J. M. Ashe, et al. A Spontaneously Arising Mutation in the DLAARN Motif of Murine ZAP-70 Abrogates Kinase Activity and Arrests Thymocyte Development. Immunity. 1997; 6(6): 663-671.
- Mortarino,M., Gelain, M.E., et al. ZAP-70 and Syk expression in canine lymphoid cells and preliminary results on leukaemia cases. Veterinary Immunology and Immunopathology. 2009; 128(4): 395-401.
- Béné, M. C. What is ZAP-70? Cytometry Part B: Clinical Cytometry 70B. 2006;(4): 204-208.
- Bukrinsky, A. and L. A. University of California. Zebrafish (Danio rerio) as a model system for human leukemia and hematopoiesis. Los Angeles, USA: University of California; 2008.
- EMBL-EBI: ZAP70_MOUSE
- NCBI: zeta-chain (TCR) associated protein kinase 70kDa, isoform CRA_a [Homo sapiens] , last accessed March 03, 2012
- ZFIN: zeta-chain (TCR) associated protein kinase , last accessed March 02, 2012
- Signalling gateway: Zap70 (Mouse), latest potential orthologs retrieved 1 Feb 2012