RBCC Red Blood Cell Collection

HBZ (HBZ2) [Confidence: low (only semi-automatic identification from reviews)]
Hemoglobin subunit zeta (HBAZ; Hemoglobin zeta chain; Zeta-globin)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P02008
ID HBAZ_HUMAN Reviewed; 142 AA.
AC P02008; Q6IBF6;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 2.
DT 22-JAN-2014, entry version 145.
DE RecName: Full=Hemoglobin subunit zeta;
DE AltName: Full=HBAZ;
DE AltName: Full=Hemoglobin zeta chain;
DE AltName: Full=Zeta-globin;
GN Name=HBZ; Synonyms=HBZ2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=6297773; DOI=10.1016/0092-8674(82)90311-7;
RA Proudfoot N.J., Gil A., Maniatis T.;
RT "The structure of the human zeta-globin gene and a closely linked,
RT nearly identical pseudogene.";
RL Cell 31:553-563(1982).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=6963223;
RA Cohen-Solal M., Authier B., Deriel J.K., Murnane M.J., Forget B.G.;
RT "Cloning and nucleotide sequence analysis of human embryonic zeta-
RT globin cDNA.";
RL DNA 1:355-363(1982).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9054936; DOI=10.1038/ng0397-252;
RA Flint J., Thomas K., Micklem G., Raynham H., Clark K., Doggett N.A.,
RA King A., Higgs D.R.;
RT "The relationship between chromosome structure and function at a human
RT telomeric region.";
RL Nat. Genet. 15:252-257(1997).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=11157797; DOI=10.1093/hmg/10.4.339;
RA Daniels R.J., Peden J.F., Lloyd C., Horsley S.W., Clark K.,
RA Tufarelli C., Kearney L., Buckle V.J., Doggett N.A., Flint J.,
RA Higgs D.R.;
RT "Sequence, structure and pathology of the fully annotated terminal 2
RT Mb of the short arm of human chromosome 16.";
RL Hum. Mol. Genet. 10:339-352(2001).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Pancreas, and Spleen;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP PROTEIN SEQUENCE OF 2-142.
RX PubMed=6179844;
RA Aschauer H., Sanguansermsri T., Braunitzer G.;
RT "Human embryonic haemoglobins. The primary structure of the zeta
RT chains.";
RL Hoppe-Seyler's Z. Physiol. Chem. 362:1159-1162(1981).
RN [9]
RP PROTEIN SEQUENCE OF 2-142.
RX PubMed=6171809; DOI=10.1073/pnas.78.10.6076;
RA Clegg J.B., Gagnon J.;
RT "Structure of the zeta chain of human embryonic hemoglobin.";
RL Proc. Natl. Acad. Sci. U.S.A. 78:6076-6080(1981).
RN [10]
RP ACETYLATION AT SER-2.
RX PubMed=6172357;
RA Aschauer H., Schaefer W., Sanguansermsri T., Braunitzer G.;
RT "Human embryonic haemoglobins. Ac-Ser-Leu-Thr-is the N-terminal
RT sequence of the zeta-chains.";
RL Hoppe-Seyler's Z. Physiol. Chem. 362:1657-1659(1981).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 2-141 IN COMPLEX WITH MOUSE
RP HBB, CLEAVAGE OF INITIATOR METHIONINE, AND ACETYLATION AT SER-2.
RX PubMed=11747442; DOI=10.1021/bi011329f;
RA Kidd R.D., Russell J.E., Watmough N.J., Baker E.N., Brittain T.;
RT "The role of beta chains in the control of the hemoglobin oxygen
RT binding function: chimeric human/mouse proteins, structure, and
RT function.";
RL Biochemistry 40:15669-15675(2001).
CC -!- FUNCTION: The zeta chain is an alpha-type chain of mammalian
CC embryonic hemoglobin, synthesized primarily in the yolk sac.
CC -!- SUBUNIT: Heterotetramer of two zeta chains and two epsilon chains
CC in early embryonic hemoglobin Gower-1; two zeta chains and two
CC gamma chains in hemoglobin Portland-1.
CC -!- TISSUE SPECIFICITY: Red blood cells.
CC -!- SIMILARITY: Belongs to the globin family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/HBZ";
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DR EMBL; J00182; AAB59406.1; -; Genomic_DNA.
DR EMBL; M24173; AAA61306.1; -; mRNA.
DR EMBL; Z84721; CAB06552.1; -; Genomic_DNA.
DR EMBL; CR456848; CAG33129.1; -; mRNA.
DR EMBL; AE006462; AAK61214.1; -; Genomic_DNA.
DR EMBL; CH471112; EAW85864.1; -; Genomic_DNA.
DR EMBL; BC027892; AAH27892.1; -; mRNA.
DR PIR; A90832; HZHU.
DR RefSeq; NP_005323.1; NM_005332.2.
DR RefSeq; XP_005255345.1; XM_005255288.1.
DR UniGene; Hs.585357; -.
DR PDB; 1JEB; X-ray; 2.10 A; A/C=2-141.
DR PDB; 3W4U; X-ray; 1.95 A; A/C/E=1-142.
DR PDBsum; 1JEB; -.
DR PDBsum; 3W4U; -.
DR ProteinModelPortal; P02008; -.
DR SMR; P02008; 2-142.
DR IntAct; P02008; 2.
DR MINT; MINT-1416153; -.
DR STRING; 9606.ENSP00000252951; -.
DR PhosphoSite; P02008; -.
DR DMDM; 122335; -.
DR PaxDb; P02008; -.
DR PeptideAtlas; P02008; -.
DR PRIDE; P02008; -.
DR DNASU; 3050; -.
DR Ensembl; ENST00000252951; ENSP00000252951; ENSG00000130656.
DR GeneID; 3050; -.
DR KEGG; hsa:3050; -.
DR UCSC; uc002cft.1; human.
DR CTD; 3050; -.
DR GeneCards; GC16P000202; -.
DR H-InvDB; HIX0059565; -.
DR HGNC; HGNC:4835; HBZ.
DR MIM; 142310; gene.
DR neXtProt; NX_P02008; -.
DR PharmGKB; PA29212; -.
DR eggNOG; NOG271358; -.
DR HOGENOM; HOG000036867; -.
DR HOVERGEN; HBG009709; -.
DR InParanoid; P02008; -.
DR KO; K13826; -.
DR OMA; VHAAWDK; -.
DR OrthoDB; EOG7KH9MP; -.
DR EvolutionaryTrace; P02008; -.
DR GeneWiki; HBZ; -.
DR GenomeRNAi; 3050; -.
DR NextBio; 12075; -.
DR PRO; PR:P02008; -.
DR Bgee; P02008; -.
DR CleanEx; HS_HBZ; -.
DR Genevestigator; P02008; -.
DR GO; GO:0005833; C:hemoglobin complex; TAS:ProtInc.
DR GO; GO:0020037; F:heme binding; IEA:InterPro.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0019825; F:oxygen binding; IEA:InterPro.
DR GO; GO:0005344; F:oxygen transporter activity; TAS:ProtInc.
DR GO; GO:0043249; P:erythrocyte maturation; IEA:Ensembl.
DR GO; GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; IEA:Ensembl.
DR Gene3D; 1.10.490.10; -; 1.
DR InterPro; IPR000971; Globin.
DR InterPro; IPR009050; Globin-like.
DR InterPro; IPR012292; Globin_dom.
DR InterPro; IPR002338; Haemoglobin_a.
DR InterPro; IPR002340; Haemoglobin_zeta.
DR Pfam; PF00042; Globin; 1.
DR PRINTS; PR00612; ALPHAHAEM.
DR PRINTS; PR00816; ZETAHAEM.
DR SUPFAM; SSF46458; SSF46458; 1.
DR PROSITE; PS01033; GLOBIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome;
KW Direct protein sequencing; Heme; Iron; Metal-binding;
KW Oxygen transport; Reference proteome; Transport.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 142 Hemoglobin subunit zeta.
FT /FTId=PRO_0000052851.
FT METAL 59 59 Iron (heme distal ligand).
FT METAL 88 88 Iron (heme proximal ligand).
FT MOD_RES 2 2 N-acetylserine.
FT HELIX 5 19
FT HELIX 22 36
FT HELIX 38 43
FT HELIX 54 72
FT HELIX 74 76
FT HELIX 77 80
FT HELIX 82 89
FT TURN 90 92
FT HELIX 97 113
FT TURN 115 117
FT HELIX 120 137
FT HELIX 139 141
SQ SEQUENCE 142 AA; 15637 MW; B62A9B825743A155 CRC64;
MSLTKTERTI IVSMWAKIST QADTIGTETL ERLFLSHPQT KTYFPHFDLH PGSAQLRAHG
SKVVAAVGDA VKSIDDIGGA LSKLSELHAY ILRVDPVNFK LLSHCLLVTL AARFPADFTA
EAHAAWDKFL SVVSSVLTEK YR
//

MIM 142310
*RECORD*
*FIELD* NO
142310
*FIELD* TI
*142310 HEMOGLOBIN--ZETA LOCUS; HBZ
;;HEMOGLOBIN ZETA;;
5-PRIME @ZETA LOCUS;;
HEMOGLOBIN ZETA-2, FORMERLY; HBZ2, FORMERLY
read more*FIELD* TX
Zeta is an early embryonic chain which is substituted for the alpha
chain in Hb Portland-1. This unique hemoglobin was found in a newborn
infant with multiple congenital anomalies and complex autosomal
chromosomal mosaicism (Capp et al., 1967). Its composition was found to
be gamma(2) X(2). It was originally thought that the X-chain might be
the epsilon chain whose synthesis persisted until after birth because of
the chromosomal anomaly; later work indicated that the X-chain is indeed
different from epsilon and therefore it is now called zeta. Hb
Portland-2 is the designation for zeta(2)-beta(2) found in stillborn
infants with homozygous alpha-thalassemia (Randhawa et al., 1984).

Melderis et al. (1974) presented evidence for the zeta chain being
homologous with the alpha chain. The zeta chains of mice, rabbits and
man showed close similarities to each other and significant similarities
to the alpha chains of these species. Kamuzora and Lehmann (1975) gave
sequence data on the human zeta chain and pointed out a close homology
to the alpha chain. Recombinant DNA experiments at Cambridge University
provided suggestions that the zeta locus may be linked to the alpha loci
(Housman, 1979).

Pressley et al. (1980) presented the findings in 2 infants with
hemoglobin Bart's hydrops fetalis syndrome (homozygous
alpha-thalassemia-1) as evidence that the 5-prime zeta locus is
functional. One of the infants had lost the 3-prime-zeta-1 gene but had
zeta-globin in the cord blood.

In the mouse, Whitney and Russell (1980) concluded that the embryonic
alpha-like gene is closely linked to the gene of adult alpha-globin. In
mouse embryos heterozygous for alpha-thalassemia, they found no decrease
in the proportion of hemoglobins containing the alpha chain as compared
to the hemoglobin containing the alpha-like embryonic globin chain.

Aschauer et al. (1981) found 57 amino acid differences between the zeta
chain and the alpha chain. This finding indicates 'a greater
phylogenetic distance' between alpha-type chains than between the
beta-type chains. Several of the zeta chain replacements are at
positions of structural and functional significance, particularly in
relation to the Bohr effect and high oxygen affinity which characterize
embryonic hemoglobins (Clegg and Gagnon, 1981). The gene order in the
HBAC (hemoglobin alpha cluster) is zeta--11.5
kb--pseudozeta--pseudoalpha--alpha-2--alpha-1. What was formerly called
zeta-2, the locus at the 5-prime end of the alpha-globin cluster, is the
functional gene.

Chung et al. (1984) concluded that deletion of 2 alpha-globin genes on
the same chromosome as in alpha-thalassemia is accompanied by the
continued expression of embryonic zeta-globin genes in adults. The
3-prime zeta-1 gene, a pseudogene, is highly homologous to the
functional 5-prime zeta-2 gene. By genomic mapping and oligonucleotide
analysis, Hill et al. (1985) found chromosomes with a zeta-2--zeta-1
rather than a zeta-2--psi-zeta-1 arrangement. Gene conversion of the
psi-zeta-1 by the psi-zeta-2 gene appears to have happened. In this
interchromosomal process the only identifiable inactivating mutation in
the psi-zeta-1 gene was removed. The zeta-2--zeta-1 arrangement was
common in all 8 populations studied representing a 'new' type of
polymorphism. Stable mRNA transcripts from the converted gene were
absent at 16 to 20 weeks of gestation when transcripts from the zeta-2
gene were readily detectable. Zeta-1 (HBZP), or pseudozeta, is very
similar to zeta-2 but has a premature termination codon.

Felice et al. (1986) found 4 types of chromosomes with a deletion
between the human embryonic zeta- and pseudo-zeta-globin genes among
2.8% of 321 black Americans. These deletions were found in combination
with alpha-globin gene deletions in trans but not in cis. No homozygotes
were identified. Hematologic data on carriers of the zeta-globin gene
deletions in association with hemoglobins AS, SS, and SC suggested that
these deletions have no effect on the function of the adult alpha-globin
genes. In eastern Polynesians, Hill et al. (1987) found a high frequency
of both triplicated zeta-gene chromosomes and a specific
alpha-thalassemia deletion. The deletion and a novel RFLP associated
with a zeta-zeta-zeta chromosome occur only in Melanesians and
Polynesians.

- PSEUDOGENES

The Hb zeta pseudogene is about 11.5 kb to the 3-prime side of the zeta
locus (Proudfoot et al., 1980). Actually there is a length polymorphism
in the segment of DNA that separates the zeta gene from its pseudogene
(Goodbourn et al., 1983). (The Hb zeta pseudogene, HBZP, was formerly
symbolized HBZ1 and referred to as the 3-prime zeta locus or the
psi-zeta locus.)

ANIMAL MODEL

Leder et al. (2005) reported that a Hbz-null mice displayed an
alpha-thalassemia-like syndrome. Embryonic survival of Hbz-null mice was
variable and strongly influenced by genetic background. The authors
identified 2 modifying loci on chromosomes 2 and 5 in the C57BL/6
background, which affected the penetrance of embryonic lethality. The
authors observed an interesting effect on somatic recombination events
in thalassemic embryos. These events occurred on multiple chromosomes in
very early embryonic cells, prior to their allocation to the germline.
Leder et al. (2005) concluded that somatic recombination events can be
transmitted to subsequent generations.

*FIELD* SA
Black (1976); Capp et al. (1970); Hecht et al. (1968); Higgs et al.
(1981)
*FIELD* RF
1. Aschauer, H.; Sanguansermsri, T.; Braunitzer, G.: Embryonale Haemoglobine
des Menschen: Die Primaerstruktur der zeta-Ketten (Human embryonic
haemoglobins: the primary structure of the zeta chains). Hoppe Seylers
Z. Physiol. Chem. 362: 1159-1162, 1981.

2. Black, J. A.: Human zeta hemoglobin chain. (Letter) Nature 261:
348 only, 1976.

3. Capp, G. L.; Rigas, D. A.; Jones, R. T.: Hemoglobin Portland 1:
a new human hemoglobin unique in structure. Science 157: 65-66,
1967.

4. Capp, G. L.; Rigas, D. A.; Jones, R. T.: Evidence for a new hemoglobin
chain (zeta chain). Nature 228: 278-280, 1970.

5. Chung, S.-W.; Wong, S. C.; Clarke, B. J.; Patterson, M.; Walker,
W. H. C.; Chui, D. H. K.: Human embryonic zeta-globin chains in adult
patients with alpha-thalassemias. Proc. Nat. Acad. Sci. 81: 6188-6191,
1984.

6. Clegg, J. B.; Gagnon, J.: Structure of the zeta chain of human
embryonic hemoglobin. Proc. Nat. Acad. Sci. 78: 6076-6080, 1981.

7. Felice, A. E.; Cleek, M. P.; Marino, E. M.; McKie, K. M.; McKie,
V. C.; Chang, B. K.; Huisman, T. H. J.: Different zeta globin gene
deletions among black Americans. Hum. Genet. 73: 221-224, 1986.

8. Goodbourn, S. E. Y.; Higgs, D. R.; Clegg, J. B.; Weatherall, D.
J.: Molecular basis of length polymorphism in the human zeta-globin
gene complex. Proc. Nat. Acad. Sci. 80: 5022-5026, 1983.

9. Hecht, F.; Jones, R. T.; Koler, R. D.: Newborn infants with Hb
Portland 1, an indicator of alpha-chain deficiency. Ann. Hum. Genet. 31:
215-218, 1968.

10. Higgs, D. R.; Pressley, L.; Aldridge, B.; Clegg, J. B.; Weatherall,
D. J.; Cao, A.; Hadjiminas, M. G.; Kattamis, C.; Metaxatou-Mavromati,
A.; Rachmilewitz, E. A.; Sophocleous, T.: Genetic and molecular diversity
in nondeletion Hb H disease. Proc. Nat. Acad. Sci. 78: 5833-5837,
1981.

11. Hill, A. V. S.; Gentile, B.; Bonnardot, J. M.; Roux, J.; Weatherall,
D. J.; Clegg, J. B.: Polynesian origins and affinities: globin gene
variants in eastern Polynesia. Am. J. Hum. Genet. 40: 453-463, 1987.

12. Hill, A. V. S.; Nicholls, R. D.; Thein, S. L.; Higgs, D. R.:
Recombination within the human embryonic zeta-globin locus: a common
zeta-zeta chromosome produced by gene conversion of the psi-zeta gene. Cell 42:
809-819, 1985.

13. Housman, D.: Personal Communication. Boston, Mass. 1979.

14. Kamuzora, H.; Lehmann, H.: Human embryonic haemoglobins including
a comparison by homology of the human zeta and alpha chains. Nature 256:
511-513, 1975.

15. Leder, A.; McMenamin, J.; Fontaine, K.; Bishop, A.; Leder, P.
: Zeta -/- thalassemic mice are affected by two modifying loci and
display unanticipated somatic recombination leading to inherited variation. Hum.
Molec. Genet. 14: 615-625, 2005.

16. Melderis, H.; Steinheider, G.; Ostertag, W.: Evidence for a unique
kind of alpha-type globin chain in early mammalian embryos. Nature 250:
774-776, 1974.

17. Pressley, L.; Higgs, D. R.; Clegg, J. B.; Weatherall, D. J.:
Gene deletions in alpha-thalassemia prove that the 5-prime zeta locus
is functional. Proc. Nat. Acad. Sci. 77: 3586-3589, 1980.

18. Proudfoot, N. J.; Shander, M. H. M.; Manley, J. L.; Gefter, M.
L.; Maniatis, T.: Structure and in vitro transcription of human globin
genes. Science 209: 1329-1336, 1980.

19. Randhawa, Z. I.; Jones, R. T.; Lie-Injo, L. E.: Separation of
the tryptic peptides and cyanogen bromide fragments of the human embryonic
zeta chains of hemoglobin Portland I and II by reverse phase high
performance liquid chromatography. Hemoglobin 8: 463-482, 1984.

20. Whitney, J. B., III; Russell, E. S.: Linkage of genes for adult
alpha-globin and embryonic alpha-like globin chains. Proc. Nat. Acad.
Sci. 77: 1087-1090, 1980.

*FIELD* CN
George E. Tiller - updated: 2/5/2008
Victor A. McKusick - edited: 2/21/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 05/20/2010
wwang: 2/12/2008
terry: 2/5/2008
mark: 2/21/1997
mimadm: 9/24/1994
carol: 4/27/1994
terry: 4/20/1994
warfield: 4/8/1994
supermim: 3/16/1992
carol: 8/30/1991