Full text data of AHSP
AHSP
(EDRF, ERAF)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Alpha-hemoglobin-stabilizing protein (Erythroid differentiation-related factor; Erythroid-associated factor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Alpha-hemoglobin-stabilizing protein (Erythroid differentiation-related factor; Erythroid-associated factor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00010257
IPI00010257 Alpha-hemoglobin stabilizing protein Act as a chaperone to prevent the harmful aggregation of alpha-hemoglobin during normal erythroid cell development. Specifically protects free alpha-hemoglobin from precipitation. It is predicted to modulate pathological states of alpha-hemoglobin excess such as beta-thalassaemia soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
IPI00010257 Alpha-hemoglobin stabilizing protein Act as a chaperone to prevent the harmful aggregation of alpha-hemoglobin during normal erythroid cell development. Specifically protects free alpha-hemoglobin from precipitation. It is predicted to modulate pathological states of alpha-hemoglobin excess such as beta-thalassaemia soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
UniProt
Q9NZD4
ID AHSP_HUMAN Reviewed; 102 AA.
AC Q9NZD4; Q8TD01;
DT 10-OCT-2002, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-2000, sequence version 1.
DT 22-JAN-2014, entry version 104.
DE RecName: Full=Alpha-hemoglobin-stabilizing protein;
DE AltName: Full=Erythroid differentiation-related factor;
DE AltName: Full=Erythroid-associated factor;
GN Name=AHSP; Synonyms=EDRF, ERAF;
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 [MRNA], AND TISSUE SPECIFICITY.
RX PubMed=11231637; DOI=10.1038/85515;
RA Miele G., Manson J., Clinton M.;
RT "A novel erythroid-specific marker of transmissible spongiform
RT encephalopathies.";
RL Nat. Med. 7:361-364(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Umbilical cord blood;
RX PubMed=11042152; DOI=10.1101/gr.140200;
RA Zhang Q.-H., Ye M., Wu X.-Y., Ren S.-X., Zhao M., Zhao C.-J., Fu G.,
RA Shen Y., Fan H.-Y., Lu G., Zhong M., Xu X.-R., Han Z.-G., Zhang J.-W.,
RA Tao J., Huang Q.-H., Zhou J., Hu G.-X., Gu J., Chen S.-J., Chen Z.;
RT "Cloning and functional analysis of cDNAs with open reading frames for
RT 300 previously undefined genes expressed in CD34+ hematopoietic
RT stem/progenitor cells.";
RL Genome Res. 10:1546-1560(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Michel U., Schulz-Schaeffer W.;
RL Submitted (JAN-2002) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Finning K., Anstee D.;
RL Submitted (FEB-2002) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [6]
RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=12066189; DOI=10.1038/nature00803;
RA Kihm A.J., Kong Y., Hong W., Russell J.E., Rouda S., Adachi K.,
RA Simon M.C., Blobel G.A., Weiss M.J.;
RT "An abundant erythroid protein that stabilizes free alpha-
RT haemoglobin.";
RL Nature 417:758-763(2002).
RN [7]
RP CHARACTERIZATION.
RX PubMed=12192002; DOI=10.1074/jbc.M206084200;
RA Gell D., Kong Y., Eaton S.A., Weiss M.J., Mackay J.P.;
RT "Biophysical characterization of the alpha-globin binding protein
RT alpha-hemoglobin stabilizing protein.";
RL J. Biol. Chem. 277:40602-40609(2002).
RN [8]
RP STRUCTURE BY NMR OF 1-90, AND X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) IN
RP COMPLEX WITH HBA.
RX PubMed=15550245; DOI=10.1016/j.cell.2004.11.025;
RA Feng L., Gell D.A., Zhou S., Gu L., Kong Y., Li J., Hu M., Yan N.,
RA Lee C., Rich A.M., Armstrong R.S., Lay P.A., Gow A.J., Weiss M.J.,
RA Mackay J.P., Shi Y.;
RT "Molecular mechanism of AHSP-mediated stabilization of alpha-
RT hemoglobin.";
RL Cell 119:629-640(2004).
RN [9]
RP STRUCTURE BY NMR OF 2-102 OF WILD TYPE AND MUTANT ALA-30.
RX PubMed=15178680; DOI=10.1074/jbc.M405016200;
RA Santiveri C.M., Perez-Canadillas J.M., Vadivelu M.K., Allen M.D.,
RA Rutherford T.J., Watkins N.A., Bycroft M.;
RT "NMR structure of the alpha-hemoglobin stabilizing protein: insights
RT into conformational heterogeneity and binding.";
RL J. Biol. Chem. 279:34963-34970(2004).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) IN COMPLEX WITH HBA.
RX PubMed=15931225; DOI=10.1038/nature03609;
RA Feng L., Zhou S., Gu L., Gell D.A., Mackay J.P., Weiss M.J., Gow A.J.,
RA Shi Y.;
RT "Structure of oxidized alpha-haemoglobin bound to AHSP reveals a
RT protective mechanism for haem.";
RL Nature 435:697-701(2005).
CC -!- FUNCTION: Acts as a chaperone to prevent the harmful aggregation
CC of alpha-hemoglobin during normal erythroid cell development.
CC Specifically protects free alpha-hemoglobin from precipitation. It
CC is predicted to modulate pathological states of alpha-hemoglobin
CC excess such as beta-thalassemia.
CC -!- SUBUNIT: Monomer. Forms a heterodimer with free alpha-hemoglobin.
CC Does not bind beta-hemoglobin nor alpha(2)beta(2) hemoglobin A.
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- TISSUE SPECIFICITY: Expressed in blood and bone marrow.
CC -!- INDUCTION: By GATA1 during erythroid maturation.
CC -!- SIMILARITY: Belongs to the AHSP family.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AF364517; AAK50856.1; -; mRNA.
DR EMBL; AF208865; AAF64279.1; -; mRNA.
DR EMBL; AY072612; AAL82894.1; -; Genomic_DNA.
DR EMBL; AF485325; AAO49381.1; -; Genomic_DNA.
DR EMBL; BC035842; AAH35842.1; -; mRNA.
DR RefSeq; NP_057717.1; NM_016633.2.
DR RefSeq; XP_005255408.1; XM_005255351.1.
DR RefSeq; XP_005255409.1; XM_005255352.1.
DR UniGene; Hs.274309; -.
DR PDB; 1W09; NMR; -; A=3-94.
DR PDB; 1W0A; NMR; -; A=3-94.
DR PDB; 1W0B; NMR; -; A=2-102.
DR PDB; 1XZY; NMR; -; A=1-90.
DR PDB; 1Y01; X-ray; 2.80 A; A=1-102.
DR PDB; 1Z8U; X-ray; 2.40 A; A/C=1-102.
DR PDB; 3IA3; X-ray; 3.20 A; A/C=1-91.
DR PDB; 3OVU; X-ray; 2.83 A; A=2-102.
DR PDBsum; 1W09; -.
DR PDBsum; 1W0A; -.
DR PDBsum; 1W0B; -.
DR PDBsum; 1XZY; -.
DR PDBsum; 1Y01; -.
DR PDBsum; 1Z8U; -.
DR PDBsum; 3IA3; -.
DR PDBsum; 3OVU; -.
DR ProteinModelPortal; Q9NZD4; -.
DR SMR; Q9NZD4; 2-91.
DR IntAct; Q9NZD4; 4.
DR MINT; MINT-1427628; -.
DR STRING; 9606.ENSP00000307199; -.
DR DMDM; 23813669; -.
DR PaxDb; Q9NZD4; -.
DR PeptideAtlas; Q9NZD4; -.
DR PRIDE; Q9NZD4; -.
DR DNASU; 51327; -.
DR Ensembl; ENST00000302312; ENSP00000307199; ENSG00000169877.
DR GeneID; 51327; -.
DR KEGG; hsa:51327; -.
DR UCSC; uc002ecj.3; human.
DR CTD; 51327; -.
DR GeneCards; GC16P031540; -.
DR HGNC; HGNC:18075; AHSP.
DR HPA; HPA040940; -.
DR MIM; 605821; gene.
DR neXtProt; NX_Q9NZD4; -.
DR PharmGKB; PA27842; -.
DR eggNOG; NOG42947; -.
DR HOGENOM; HOG000030915; -.
DR HOVERGEN; HBG023495; -.
DR InParanoid; Q9NZD4; -.
DR OMA; GMKEFNV; -.
DR OrthoDB; EOG7TF7CW; -.
DR PhylomeDB; Q9NZD4; -.
DR ChiTaRS; AHSP; human.
DR EvolutionaryTrace; Q9NZD4; -.
DR GeneWiki; ERAF; -.
DR GenomeRNAi; 51327; -.
DR NextBio; 54729; -.
DR PRO; PR:Q9NZD4; -.
DR ArrayExpress; Q9NZD4; -.
DR Bgee; Q9NZD4; -.
DR CleanEx; HS_ERAF; -.
DR Genevestigator; Q9NZD4; -.
DR GO; GO:0005833; C:hemoglobin complex; NAS:UniProtKB.
DR GO; GO:0030492; F:hemoglobin binding; NAS:UniProtKB.
DR GO; GO:0051082; F:unfolded protein binding; NAS:UniProtKB.
DR GO; GO:0020027; P:hemoglobin metabolic process; NAS:UniProtKB.
DR GO; GO:0030097; P:hemopoiesis; NAS:UniProtKB.
DR GO; GO:0006457; P:protein folding; IEA:InterPro.
DR GO; GO:0050821; P:protein stabilization; IEA:InterPro.
DR Gene3D; 1.20.58.420; -; 1.
DR InterPro; IPR015317; A_Hb_stabilising_prot.
DR PANTHER; PTHR15914; PTHR15914; 1.
DR Pfam; PF09236; AHSP; 1.
DR ProDom; PD285427; A_Hb_stabilising_prot; 1.
DR SUPFAM; SSF109751; SSF109751; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Chaperone; Complete proteome; Cytoplasm; Polymorphism;
KW Reference proteome.
FT CHAIN 1 102 Alpha-hemoglobin-stabilizing protein.
FT /FTId=PRO_0000064509.
FT VARIANT 100 100 P -> T (in dbSNP:rs36018996).
FT /FTId=VAR_050650.
FT CONFLICT 32 32 V -> A (in Ref. 3; AAL82894).
FT CONFLICT 87 87 D -> N (in Ref. 3; AAL82894).
FT HELIX 5 23
FT HELIX 27 29
FT HELIX 34 52
FT TURN 53 55
FT HELIX 60 86
FT STRAND 97 99
SQ SEQUENCE 102 AA; 11840 MW; 275DDF8BC670EF20 CRC64;
MALLKANKDL ISAGLKEFSV LLNQQVFNDP LVSEEDMVTV VEDWMNFYIN YYRQQVTGEP
QERDKALQEL RQELNTLANP FLAKYRDFLK SHELPSHPPP SS
//
ID AHSP_HUMAN Reviewed; 102 AA.
AC Q9NZD4; Q8TD01;
DT 10-OCT-2002, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-2000, sequence version 1.
DT 22-JAN-2014, entry version 104.
DE RecName: Full=Alpha-hemoglobin-stabilizing protein;
DE AltName: Full=Erythroid differentiation-related factor;
DE AltName: Full=Erythroid-associated factor;
GN Name=AHSP; Synonyms=EDRF, ERAF;
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 [MRNA], AND TISSUE SPECIFICITY.
RX PubMed=11231637; DOI=10.1038/85515;
RA Miele G., Manson J., Clinton M.;
RT "A novel erythroid-specific marker of transmissible spongiform
RT encephalopathies.";
RL Nat. Med. 7:361-364(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Umbilical cord blood;
RX PubMed=11042152; DOI=10.1101/gr.140200;
RA Zhang Q.-H., Ye M., Wu X.-Y., Ren S.-X., Zhao M., Zhao C.-J., Fu G.,
RA Shen Y., Fan H.-Y., Lu G., Zhong M., Xu X.-R., Han Z.-G., Zhang J.-W.,
RA Tao J., Huang Q.-H., Zhou J., Hu G.-X., Gu J., Chen S.-J., Chen Z.;
RT "Cloning and functional analysis of cDNAs with open reading frames for
RT 300 previously undefined genes expressed in CD34+ hematopoietic
RT stem/progenitor cells.";
RL Genome Res. 10:1546-1560(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Michel U., Schulz-Schaeffer W.;
RL Submitted (JAN-2002) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Finning K., Anstee D.;
RL Submitted (FEB-2002) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [6]
RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=12066189; DOI=10.1038/nature00803;
RA Kihm A.J., Kong Y., Hong W., Russell J.E., Rouda S., Adachi K.,
RA Simon M.C., Blobel G.A., Weiss M.J.;
RT "An abundant erythroid protein that stabilizes free alpha-
RT haemoglobin.";
RL Nature 417:758-763(2002).
RN [7]
RP CHARACTERIZATION.
RX PubMed=12192002; DOI=10.1074/jbc.M206084200;
RA Gell D., Kong Y., Eaton S.A., Weiss M.J., Mackay J.P.;
RT "Biophysical characterization of the alpha-globin binding protein
RT alpha-hemoglobin stabilizing protein.";
RL J. Biol. Chem. 277:40602-40609(2002).
RN [8]
RP STRUCTURE BY NMR OF 1-90, AND X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) IN
RP COMPLEX WITH HBA.
RX PubMed=15550245; DOI=10.1016/j.cell.2004.11.025;
RA Feng L., Gell D.A., Zhou S., Gu L., Kong Y., Li J., Hu M., Yan N.,
RA Lee C., Rich A.M., Armstrong R.S., Lay P.A., Gow A.J., Weiss M.J.,
RA Mackay J.P., Shi Y.;
RT "Molecular mechanism of AHSP-mediated stabilization of alpha-
RT hemoglobin.";
RL Cell 119:629-640(2004).
RN [9]
RP STRUCTURE BY NMR OF 2-102 OF WILD TYPE AND MUTANT ALA-30.
RX PubMed=15178680; DOI=10.1074/jbc.M405016200;
RA Santiveri C.M., Perez-Canadillas J.M., Vadivelu M.K., Allen M.D.,
RA Rutherford T.J., Watkins N.A., Bycroft M.;
RT "NMR structure of the alpha-hemoglobin stabilizing protein: insights
RT into conformational heterogeneity and binding.";
RL J. Biol. Chem. 279:34963-34970(2004).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) IN COMPLEX WITH HBA.
RX PubMed=15931225; DOI=10.1038/nature03609;
RA Feng L., Zhou S., Gu L., Gell D.A., Mackay J.P., Weiss M.J., Gow A.J.,
RA Shi Y.;
RT "Structure of oxidized alpha-haemoglobin bound to AHSP reveals a
RT protective mechanism for haem.";
RL Nature 435:697-701(2005).
CC -!- FUNCTION: Acts as a chaperone to prevent the harmful aggregation
CC of alpha-hemoglobin during normal erythroid cell development.
CC Specifically protects free alpha-hemoglobin from precipitation. It
CC is predicted to modulate pathological states of alpha-hemoglobin
CC excess such as beta-thalassemia.
CC -!- SUBUNIT: Monomer. Forms a heterodimer with free alpha-hemoglobin.
CC Does not bind beta-hemoglobin nor alpha(2)beta(2) hemoglobin A.
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- TISSUE SPECIFICITY: Expressed in blood and bone marrow.
CC -!- INDUCTION: By GATA1 during erythroid maturation.
CC -!- SIMILARITY: Belongs to the AHSP family.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AF364517; AAK50856.1; -; mRNA.
DR EMBL; AF208865; AAF64279.1; -; mRNA.
DR EMBL; AY072612; AAL82894.1; -; Genomic_DNA.
DR EMBL; AF485325; AAO49381.1; -; Genomic_DNA.
DR EMBL; BC035842; AAH35842.1; -; mRNA.
DR RefSeq; NP_057717.1; NM_016633.2.
DR RefSeq; XP_005255408.1; XM_005255351.1.
DR RefSeq; XP_005255409.1; XM_005255352.1.
DR UniGene; Hs.274309; -.
DR PDB; 1W09; NMR; -; A=3-94.
DR PDB; 1W0A; NMR; -; A=3-94.
DR PDB; 1W0B; NMR; -; A=2-102.
DR PDB; 1XZY; NMR; -; A=1-90.
DR PDB; 1Y01; X-ray; 2.80 A; A=1-102.
DR PDB; 1Z8U; X-ray; 2.40 A; A/C=1-102.
DR PDB; 3IA3; X-ray; 3.20 A; A/C=1-91.
DR PDB; 3OVU; X-ray; 2.83 A; A=2-102.
DR PDBsum; 1W09; -.
DR PDBsum; 1W0A; -.
DR PDBsum; 1W0B; -.
DR PDBsum; 1XZY; -.
DR PDBsum; 1Y01; -.
DR PDBsum; 1Z8U; -.
DR PDBsum; 3IA3; -.
DR PDBsum; 3OVU; -.
DR ProteinModelPortal; Q9NZD4; -.
DR SMR; Q9NZD4; 2-91.
DR IntAct; Q9NZD4; 4.
DR MINT; MINT-1427628; -.
DR STRING; 9606.ENSP00000307199; -.
DR DMDM; 23813669; -.
DR PaxDb; Q9NZD4; -.
DR PeptideAtlas; Q9NZD4; -.
DR PRIDE; Q9NZD4; -.
DR DNASU; 51327; -.
DR Ensembl; ENST00000302312; ENSP00000307199; ENSG00000169877.
DR GeneID; 51327; -.
DR KEGG; hsa:51327; -.
DR UCSC; uc002ecj.3; human.
DR CTD; 51327; -.
DR GeneCards; GC16P031540; -.
DR HGNC; HGNC:18075; AHSP.
DR HPA; HPA040940; -.
DR MIM; 605821; gene.
DR neXtProt; NX_Q9NZD4; -.
DR PharmGKB; PA27842; -.
DR eggNOG; NOG42947; -.
DR HOGENOM; HOG000030915; -.
DR HOVERGEN; HBG023495; -.
DR InParanoid; Q9NZD4; -.
DR OMA; GMKEFNV; -.
DR OrthoDB; EOG7TF7CW; -.
DR PhylomeDB; Q9NZD4; -.
DR ChiTaRS; AHSP; human.
DR EvolutionaryTrace; Q9NZD4; -.
DR GeneWiki; ERAF; -.
DR GenomeRNAi; 51327; -.
DR NextBio; 54729; -.
DR PRO; PR:Q9NZD4; -.
DR ArrayExpress; Q9NZD4; -.
DR Bgee; Q9NZD4; -.
DR CleanEx; HS_ERAF; -.
DR Genevestigator; Q9NZD4; -.
DR GO; GO:0005833; C:hemoglobin complex; NAS:UniProtKB.
DR GO; GO:0030492; F:hemoglobin binding; NAS:UniProtKB.
DR GO; GO:0051082; F:unfolded protein binding; NAS:UniProtKB.
DR GO; GO:0020027; P:hemoglobin metabolic process; NAS:UniProtKB.
DR GO; GO:0030097; P:hemopoiesis; NAS:UniProtKB.
DR GO; GO:0006457; P:protein folding; IEA:InterPro.
DR GO; GO:0050821; P:protein stabilization; IEA:InterPro.
DR Gene3D; 1.20.58.420; -; 1.
DR InterPro; IPR015317; A_Hb_stabilising_prot.
DR PANTHER; PTHR15914; PTHR15914; 1.
DR Pfam; PF09236; AHSP; 1.
DR ProDom; PD285427; A_Hb_stabilising_prot; 1.
DR SUPFAM; SSF109751; SSF109751; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Chaperone; Complete proteome; Cytoplasm; Polymorphism;
KW Reference proteome.
FT CHAIN 1 102 Alpha-hemoglobin-stabilizing protein.
FT /FTId=PRO_0000064509.
FT VARIANT 100 100 P -> T (in dbSNP:rs36018996).
FT /FTId=VAR_050650.
FT CONFLICT 32 32 V -> A (in Ref. 3; AAL82894).
FT CONFLICT 87 87 D -> N (in Ref. 3; AAL82894).
FT HELIX 5 23
FT HELIX 27 29
FT HELIX 34 52
FT TURN 53 55
FT HELIX 60 86
FT STRAND 97 99
SQ SEQUENCE 102 AA; 11840 MW; 275DDF8BC670EF20 CRC64;
MALLKANKDL ISAGLKEFSV LLNQQVFNDP LVSEEDMVTV VEDWMNFYIN YYRQQVTGEP
QERDKALQEL RQELNTLANP FLAKYRDFLK SHELPSHPPP SS
//
MIM
605821
*RECORD*
*FIELD* NO
605821
*FIELD* TI
*605821 ERYTHROID-ASSOCIATED FACTOR; ERAF
;;ERYTHROID DIFFERENTIATION-RELATED FACTOR; EDRF;;
read moreALPHA-HEMOGLOBIN STABILIZING PROTEIN; AHSP
*FIELD* TX
CLONING
The EDRF gene expresses a transcript that is confined to the erythroid
lineage and is downregulated in transmissible spongiform
encephalopathies (TSEs). To identify molecular markers of TSEs in
noncentral nervous system tissues, Miele et al. (2001) compared gene
expression in spleens of scrapie-infected and uninfected mice. Miele et
al. (2001) used the differential display RT-PCR procedure to
specifically identify genes differentially expressed as a result of TSE
infection. They identified 1 cDNA representing a transcript that clearly
showed a decrease in expression level in spleens from scrapie-infected
C57BL mice. This sequence, called 'erythroid differentiation-related
factor' (EDRF), represents a transcript of approximately 0.5 kb with a
predicted open reading frame (ORF) of 102 amino acids. Northern blot
analysis of RNA isolated from spleens of scrapie-infected and control
mice confirmed that levels of EDRF transcript are dramatically decreased
at the terminal stages of disease. The effect on EDRF transcript levels
in spleen is first evident during the early stages of disease and
becomes more pronounced with progression of disease. Northern blot
analysis of RNA from spleens of both mice and hamsters infected with a
number of different strains of TSE agents confirmed the substantial
decrease in levels of EDRF transcript. In mice, EDRF is normally
expressed only in spleen, bone marrow, and blood, with highest levels in
bone marrow. Northern blot analysis of human tissue revealed that EDRF
expression was confined to blood and bone marrow, with no expression
detectable in spleen. Reduced EDRF expression was also detected in
BSE-infected cattle and scrapie-infected sheep. EDRF expression is
confined to the erythroid lineage, with higher levels of expression in
blast-forming (BFU-E), colony-forming (CFU-E), and maturing erythroid
(TER-119+) cells.
By using a screen for genes induced by the essential erythroid
transcription factor GATA1 (305371), Kihm et al. (2002) identified the
ERAF protein as one that stabilizes free alpha-hemoglobin and renamed it
'alpha-hemoglobin stabilizing protein,' or AHSP, on the basis of this
function. AHSP is an abundant erythroid-specific protein that forms a
stable complex with free alpha-hemoglobin but not with beta-hemoglobin
or hemoglobin A (alpha2-beta2). Moreover, AHSP specifically protects
free alpha-hemoglobin from precipitation in solution and in live cells.
Kihm et al. (2002) predicted that AHSP gene dosage would modulate
pathologic states of alpha-hemoglobin excess such as beta-thalassemia.
Although beta-thalassemia is considered to be a classic monogenic
disease, there is considerable clinical variability between patients who
inherit identical mutations in the beta-globin gene (HBB; 141900),
suggesting that there may be a variety of genetic determinants
influencing the clinical phenotype. It has been proposed that alleles
altering the levels or function of AHSP might account for some of the
clinical variability observed in patients with beta-thalassemia (Kihm et
al., 2002; Luzatto and Notaro, 2002). To address this hypothesis,
Viprakasit et al. (2004) studied 120 Thai patients with Hb E
(141900.0071) with mild, moderate, or severe clinical phenotypes. Using
gene mapping, direct genomic sequencing, and extended haplotype
analysis, they found no mutation or specific association between
haplotypes of AHSP and disease severity in these patients, suggesting
that AHSP is not a disease modifier in Hb E. Viprakasit et al. (2004)
pointed out that the AHSP gene is located on chromosome 16, and contains
3 exons.
BIOCHEMICAL FEATURES
- Crystal Structure
Hemoglobin A (HbA), the oxygen delivery system in humans, comprises 2
alpha and 2 beta subunits. Free alpha-Hb is unstable, and its
precipitation contributes to the pathophysiology of beta-thalassemia. In
erythrocytes, AHSP binds alpha-Hb and inhibits its precipitation. Feng
et al. (2004) determined the crystal structure of AHSP bound to
Fe(II)-alpha-Hb. AHSP specifically recognized the G and H helices of
alpha-Hb through a hydrophobic interface that largely recapitulated the
alpha-1-beta-1 interface of hemoglobin. The AHSP-alpha-Hb interactions
were extensive but suboptimal, explaining why beta-hemoglobin can
competitively displace AHSP to form HbA. The Fe(II)-heme group in
AHSP-bound alpha-Hb was coordinated by the distal but not the proximal
histidine. Binding to AHSP facilitated the conversion of oxy-alpha-Hb to
a deoxygenated, oxidized (Fe(III)), nonreactive form in which all 6
coordinate positions were occupied. These observations revealed the
molecular mechanisms by which AHSP stabilizes free alpha-Hb.
Feng et al. (2005) reported the crystal structure of ferric alpha-Hb
complexed with AHSP at 2.4-angstrom resolution. Their findings revealed
a striking bis-histidyl configuration in which both the proximal and the
distal histidines coordinate the heme iron atom. To attain this unusual
conformation, segments of the alpha-Hb undergo drastic structural
rearrangements, including the repositioning of several alpha-helices.
Moreover, conversion to the ferric bis-histidine configuration strongly
and specifically inhibits redox chemistry catalysis and heme loss from
alpha-Hb. The observed structural changes, which impaired the chemical
reactivity of heme iron, explained how AHSP stabilizes alpha-Hb and
prevents its damaging effects in cells.
ANIMAL MODEL
Kihm et al. (2002) generated mice deficient in AHSP. Ahsp -/- mice were
born at expected mendelian ratios and displayed grossly normal growth
and development. Although the mice exhibited normal blood hemoglobin
concentrations and hematocrits, their reticulocyte counts were elevated
about 3-fold, indicating a shortened erythrocyte half-life. Ahsp -/-
erythrocytes exhibited an abnormal spiculated morphology that has also
been observed in erythroid cells of beta-thalassemic mice. Moreover,
Ahsp -/- erythrocytes contained denatured hemoglobin inclusions (Heinz
bodies) that stained with crystal violet. Thus, the loss of AHSP leads
to defective hemoglobin metabolism in vivo. The reticulocyte counts in
Ahsp +/- mice were mildly elevated, indicating that AHSP
haploinsufficiency may produce a subtle erythroid phenotype.
Kong et al. (2004) performed biochemical studies in Ahsp null mice and
found that Ahsp -/- erythrocytes were short-lived and contained
hemoglobin precipitates and reactive oxygen species with evidence of
oxidative damage. Erythroid precursors were elevated in number but
exhibited increased apoptosis. Purified recombinant AHSP inhibited the
production of reactive oxygen species by alpha-hemoglobin in solution.
Loss of Ahsp worsened the phenotype in beta-thalassemic mice. Kong et
al. (2004) proposed an essential function for AHSP, both in normal
erythropoiesis and to a greater extent in beta-thalassemia, in binding
alpha-hemoglobin transiently to stabilize its conformation and render it
biochemically inert prior to hemoglobin A assembly.
*FIELD* RF
1. Feng, L.; Gell, D. A.; Zhou, S.; Gu, L.; Kong, Y.; Li, J.; Hu,
M.; Yan, N.; Lee, C.; Rich, A. M.; Armstrong, R. S.; Lay, P. A.; Gow,
A. J.; Weiss, M. J.; Mackay, J. P.; Shi, Y.: Molecular mechanism
of AHSP-mediated stabilization of alpha-hemoglobin. Cell 119: 629-640,
2004.
2. Feng, L.; Zhou, S.; Gu, L.; Gell, D. A.; Mackay, J. P.; Weiss,
M. J.; Gow, A. J.; Shi, Y.: Structure of oxidized alpha-haemoglobin
bound to AHSP reveals a protective mechanism for haem. (Letter) Nature 435:
697-701, 2005.
3. Kihm, A. J.; Kong, Y.; Hong, W.; Russell, J. E.; Rouda, S.; Adachi,
K.; Simon, M. C.; Blobel, G. A.; Weiss, M. J.: An abundant erythroid
protein that stabilizes free alpha-haemoglobin. Nature 417: 758-763,
2002.
4. Kong, Y.; Zhou, S.; Kihm, A. J.; Katein, A. M.; Yu, X.; Gell, D.
A.; Mackay, J. P.; Adachi, K.; Foster-Brown, L.; Louden, C. S.; Gow,
A. J.; Weiss, M. J.: Loss of alpha-hemoglobin-stabilizing protein
impairs erythropoiesis and exacerbates beta-thalassemia. J. Clin.
Invest. 114: 1457-1466, 2004.
5. Luzatto, L.; Notaro, R.: Haemoglobin's chaperone. Nature 417:
703-705, 2002.
6. Miele, G.; Manson, J.; Clinton, M.: A novel erythroid-specific
marker of transmissible spongiform encephalopathies. Nature Med. 7:
361-364, 2001.
7. Viprakasit, V.; Tanphaichitr, V. S.; Chinchang, W.; Sangkla, P.;
Weiss, M. J.; Higgs, D. R.: Evaluation of alpha hemoglobin stabilizing
protein (AHSP) as a genetic modifier in patients with beta thalassemia. Blood 103:
3296-3299, 2004.
*FIELD* CN
Ada Hamosh - updated: 6/15/2005
Marla J. F. O'Neill - updated: 1/19/2005
Stylianos E. Antonarakis - updated: 1/4/2005
Victor A. McKusick - updated: 10/4/2004
Ada Hamosh - updated: 7/10/2002
*FIELD* CD
Ada Hamosh: 4/5/2001
*FIELD* ED
alopez: 06/16/2005
terry: 6/15/2005
terry: 2/10/2005
carol: 1/20/2005
terry: 1/19/2005
mgross: 1/4/2005
tkritzer: 10/7/2004
terry: 10/4/2004
alopez: 7/11/2002
terry: 7/10/2002
alopez: 2/19/2002
alopez: 4/5/2001
*RECORD*
*FIELD* NO
605821
*FIELD* TI
*605821 ERYTHROID-ASSOCIATED FACTOR; ERAF
;;ERYTHROID DIFFERENTIATION-RELATED FACTOR; EDRF;;
read moreALPHA-HEMOGLOBIN STABILIZING PROTEIN; AHSP
*FIELD* TX
CLONING
The EDRF gene expresses a transcript that is confined to the erythroid
lineage and is downregulated in transmissible spongiform
encephalopathies (TSEs). To identify molecular markers of TSEs in
noncentral nervous system tissues, Miele et al. (2001) compared gene
expression in spleens of scrapie-infected and uninfected mice. Miele et
al. (2001) used the differential display RT-PCR procedure to
specifically identify genes differentially expressed as a result of TSE
infection. They identified 1 cDNA representing a transcript that clearly
showed a decrease in expression level in spleens from scrapie-infected
C57BL mice. This sequence, called 'erythroid differentiation-related
factor' (EDRF), represents a transcript of approximately 0.5 kb with a
predicted open reading frame (ORF) of 102 amino acids. Northern blot
analysis of RNA isolated from spleens of scrapie-infected and control
mice confirmed that levels of EDRF transcript are dramatically decreased
at the terminal stages of disease. The effect on EDRF transcript levels
in spleen is first evident during the early stages of disease and
becomes more pronounced with progression of disease. Northern blot
analysis of RNA from spleens of both mice and hamsters infected with a
number of different strains of TSE agents confirmed the substantial
decrease in levels of EDRF transcript. In mice, EDRF is normally
expressed only in spleen, bone marrow, and blood, with highest levels in
bone marrow. Northern blot analysis of human tissue revealed that EDRF
expression was confined to blood and bone marrow, with no expression
detectable in spleen. Reduced EDRF expression was also detected in
BSE-infected cattle and scrapie-infected sheep. EDRF expression is
confined to the erythroid lineage, with higher levels of expression in
blast-forming (BFU-E), colony-forming (CFU-E), and maturing erythroid
(TER-119+) cells.
By using a screen for genes induced by the essential erythroid
transcription factor GATA1 (305371), Kihm et al. (2002) identified the
ERAF protein as one that stabilizes free alpha-hemoglobin and renamed it
'alpha-hemoglobin stabilizing protein,' or AHSP, on the basis of this
function. AHSP is an abundant erythroid-specific protein that forms a
stable complex with free alpha-hemoglobin but not with beta-hemoglobin
or hemoglobin A (alpha2-beta2). Moreover, AHSP specifically protects
free alpha-hemoglobin from precipitation in solution and in live cells.
Kihm et al. (2002) predicted that AHSP gene dosage would modulate
pathologic states of alpha-hemoglobin excess such as beta-thalassemia.
Although beta-thalassemia is considered to be a classic monogenic
disease, there is considerable clinical variability between patients who
inherit identical mutations in the beta-globin gene (HBB; 141900),
suggesting that there may be a variety of genetic determinants
influencing the clinical phenotype. It has been proposed that alleles
altering the levels or function of AHSP might account for some of the
clinical variability observed in patients with beta-thalassemia (Kihm et
al., 2002; Luzatto and Notaro, 2002). To address this hypothesis,
Viprakasit et al. (2004) studied 120 Thai patients with Hb E
(141900.0071) with mild, moderate, or severe clinical phenotypes. Using
gene mapping, direct genomic sequencing, and extended haplotype
analysis, they found no mutation or specific association between
haplotypes of AHSP and disease severity in these patients, suggesting
that AHSP is not a disease modifier in Hb E. Viprakasit et al. (2004)
pointed out that the AHSP gene is located on chromosome 16, and contains
3 exons.
BIOCHEMICAL FEATURES
- Crystal Structure
Hemoglobin A (HbA), the oxygen delivery system in humans, comprises 2
alpha and 2 beta subunits. Free alpha-Hb is unstable, and its
precipitation contributes to the pathophysiology of beta-thalassemia. In
erythrocytes, AHSP binds alpha-Hb and inhibits its precipitation. Feng
et al. (2004) determined the crystal structure of AHSP bound to
Fe(II)-alpha-Hb. AHSP specifically recognized the G and H helices of
alpha-Hb through a hydrophobic interface that largely recapitulated the
alpha-1-beta-1 interface of hemoglobin. The AHSP-alpha-Hb interactions
were extensive but suboptimal, explaining why beta-hemoglobin can
competitively displace AHSP to form HbA. The Fe(II)-heme group in
AHSP-bound alpha-Hb was coordinated by the distal but not the proximal
histidine. Binding to AHSP facilitated the conversion of oxy-alpha-Hb to
a deoxygenated, oxidized (Fe(III)), nonreactive form in which all 6
coordinate positions were occupied. These observations revealed the
molecular mechanisms by which AHSP stabilizes free alpha-Hb.
Feng et al. (2005) reported the crystal structure of ferric alpha-Hb
complexed with AHSP at 2.4-angstrom resolution. Their findings revealed
a striking bis-histidyl configuration in which both the proximal and the
distal histidines coordinate the heme iron atom. To attain this unusual
conformation, segments of the alpha-Hb undergo drastic structural
rearrangements, including the repositioning of several alpha-helices.
Moreover, conversion to the ferric bis-histidine configuration strongly
and specifically inhibits redox chemistry catalysis and heme loss from
alpha-Hb. The observed structural changes, which impaired the chemical
reactivity of heme iron, explained how AHSP stabilizes alpha-Hb and
prevents its damaging effects in cells.
ANIMAL MODEL
Kihm et al. (2002) generated mice deficient in AHSP. Ahsp -/- mice were
born at expected mendelian ratios and displayed grossly normal growth
and development. Although the mice exhibited normal blood hemoglobin
concentrations and hematocrits, their reticulocyte counts were elevated
about 3-fold, indicating a shortened erythrocyte half-life. Ahsp -/-
erythrocytes exhibited an abnormal spiculated morphology that has also
been observed in erythroid cells of beta-thalassemic mice. Moreover,
Ahsp -/- erythrocytes contained denatured hemoglobin inclusions (Heinz
bodies) that stained with crystal violet. Thus, the loss of AHSP leads
to defective hemoglobin metabolism in vivo. The reticulocyte counts in
Ahsp +/- mice were mildly elevated, indicating that AHSP
haploinsufficiency may produce a subtle erythroid phenotype.
Kong et al. (2004) performed biochemical studies in Ahsp null mice and
found that Ahsp -/- erythrocytes were short-lived and contained
hemoglobin precipitates and reactive oxygen species with evidence of
oxidative damage. Erythroid precursors were elevated in number but
exhibited increased apoptosis. Purified recombinant AHSP inhibited the
production of reactive oxygen species by alpha-hemoglobin in solution.
Loss of Ahsp worsened the phenotype in beta-thalassemic mice. Kong et
al. (2004) proposed an essential function for AHSP, both in normal
erythropoiesis and to a greater extent in beta-thalassemia, in binding
alpha-hemoglobin transiently to stabilize its conformation and render it
biochemically inert prior to hemoglobin A assembly.
*FIELD* RF
1. Feng, L.; Gell, D. A.; Zhou, S.; Gu, L.; Kong, Y.; Li, J.; Hu,
M.; Yan, N.; Lee, C.; Rich, A. M.; Armstrong, R. S.; Lay, P. A.; Gow,
A. J.; Weiss, M. J.; Mackay, J. P.; Shi, Y.: Molecular mechanism
of AHSP-mediated stabilization of alpha-hemoglobin. Cell 119: 629-640,
2004.
2. Feng, L.; Zhou, S.; Gu, L.; Gell, D. A.; Mackay, J. P.; Weiss,
M. J.; Gow, A. J.; Shi, Y.: Structure of oxidized alpha-haemoglobin
bound to AHSP reveals a protective mechanism for haem. (Letter) Nature 435:
697-701, 2005.
3. Kihm, A. J.; Kong, Y.; Hong, W.; Russell, J. E.; Rouda, S.; Adachi,
K.; Simon, M. C.; Blobel, G. A.; Weiss, M. J.: An abundant erythroid
protein that stabilizes free alpha-haemoglobin. Nature 417: 758-763,
2002.
4. Kong, Y.; Zhou, S.; Kihm, A. J.; Katein, A. M.; Yu, X.; Gell, D.
A.; Mackay, J. P.; Adachi, K.; Foster-Brown, L.; Louden, C. S.; Gow,
A. J.; Weiss, M. J.: Loss of alpha-hemoglobin-stabilizing protein
impairs erythropoiesis and exacerbates beta-thalassemia. J. Clin.
Invest. 114: 1457-1466, 2004.
5. Luzatto, L.; Notaro, R.: Haemoglobin's chaperone. Nature 417:
703-705, 2002.
6. Miele, G.; Manson, J.; Clinton, M.: A novel erythroid-specific
marker of transmissible spongiform encephalopathies. Nature Med. 7:
361-364, 2001.
7. Viprakasit, V.; Tanphaichitr, V. S.; Chinchang, W.; Sangkla, P.;
Weiss, M. J.; Higgs, D. R.: Evaluation of alpha hemoglobin stabilizing
protein (AHSP) as a genetic modifier in patients with beta thalassemia. Blood 103:
3296-3299, 2004.
*FIELD* CN
Ada Hamosh - updated: 6/15/2005
Marla J. F. O'Neill - updated: 1/19/2005
Stylianos E. Antonarakis - updated: 1/4/2005
Victor A. McKusick - updated: 10/4/2004
Ada Hamosh - updated: 7/10/2002
*FIELD* CD
Ada Hamosh: 4/5/2001
*FIELD* ED
alopez: 06/16/2005
terry: 6/15/2005
terry: 2/10/2005
carol: 1/20/2005
terry: 1/19/2005
mgross: 1/4/2005
tkritzer: 10/7/2004
terry: 10/4/2004
alopez: 7/11/2002
terry: 7/10/2002
alopez: 2/19/2002
alopez: 4/5/2001