The gene encoding the human class II antigen-associated gamma chain is located on chromosome 5.
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Chromosome Mapping↗
Biomedical subjects
L Rask
Publications and source records attributed to L Rask.
Genomic hybridization with class II transplantation antigen cDNA probes as a complementary technique in tissue typing.
Hybridizations of HLA-DR and DC transplantation antigen beta chain cDNA probes to restriction enzyme digested genomic DNA were examined in regard to their potential in tissue typing. DNA from cells, typed by cellular techniques to be homozygous for the specificities Dw 1 to 8, gives rise to unique fragment patterns for each specificity. Hybridizations to DNA from unrelated individuals serologically typed to be DR identical occasionally reveal genetic differences in the class II antigen region, notably with the DC beta cDNA probe. In contrast, hybridizations to DNA from monozygotic twins displayed completely identical patterns with both types of probes. From these data it seems reasonable to conclude that genomic hybridizations with class II antigen probes will be useful in the definition of new class II antigen loci and alleles, in determination of paternity, in studies of class II antigen linked diseases and as a complementary method in conventional tissue typing.
Alleles↗
Signal sequences distinguish class II histocompatibility antigen beta chains of different loci.
The signal sequences of two HLA-DR beta chains and the DR alpha chain were determined. In addition, the major part of a DC beta-chain signal sequence was also elucidated. The data were obtained by combining amino acid sequence analyses of isolated alpha and beta chains with nucleotide sequencing of four cDNA clones. All signal sequences comprise 25 amino acids or more. The two HLA-DR beta-chain signal sequences are identical and exhibit only marginal homology to the DC beta-chain signal sequence. No homology is apparent between alpha- and beta-chain signal sequences. The differences in the signal sequences of the DR and DC beta chains suggest that these sequences may be used to assign beta chains to different loci of the human major histocompatibility complex.
Amino Acid Sequence↗
The complete nucleotide sequence of the I-E alpha d immune response gene.
We have isolated and sequenced the complete murine I-E alpha immune response gene of the H-2db haplotype. The I-E alpha d gene consists of 5300 basepairs and is organized into five or possibly six exons that correspond to different domains of the alpha chain. The amino acid sequence deduced from the I-E alpha gene shows 75% homology to its human counterpart, the HLA-DR alpha chain. The absence of I-E antigen in H-2 mice is due to lack of E alpha chain synthesis. We show here that this defect is caused by a deletion in the 5' end of the I-E alpha b gene.
Amino Acid Sequence↗
HLA-D region beta-chain DNA endonuclease fragments differ between HLA-DR identical healthy and insulin-dependent diabetic individuals.
The human HLA-D histocompatibility region encodes class II antigens each of which consists of two polypeptide chains (alpha and beta) inserted in the plasma membrane. These molecules are implicated in the regulation of the immune response but several human diseases are also found to be associated with certain HLA-DR antigens. The occurrence of insulin-dependent (type I) diabetes (IDDM) is strongly associated with HLA-DR3 and/or 4 (ref. 5). The class II antigens, however, show a marked genetic polymorphism associated with the beta-chains which seem, from hybridization studies, to be encoded by several genes. We have therefore used the beta-chain cDNA probe, pDR-beta-1 (refs 8, 10) to test whether there are differences in hybridization pattern between DNA from healthy individuals and diabetic patients, after digestion with restriction endonucleases. Among the HLA-DR 4 and 3/4 individuals, the IDDM patients showed an increased frequency of a PstI 18 kilobase (kb) fragment. A BamHI 3.7 kb fragment, frequent among controls (30-40%), was rarely detected in the IDDM patients (0-2%). These differences may be related to susceptibility to develop the disease.
DNA Restriction Enzymes↗
Human class II major histocompatibility antigen beta-chains are derived from at least three loci.
Class II antigens of the major histocompatibility complex (MHC) consist of two glycosylated, membrane-integrated polypeptide chains. These cell surface-expressed molecules are involved in several immunobiological events involving cell-cell interactions, most of which seem to require that genetically identical class II antigens, or other molecules controlled by the same region of the MHC, are expressed on the interacting cells. The extensive genetic polymorphism of the class II antigens has rendered analyses in the human system of the number of non-allelic species of class II antigens difficult, although several laboratories have reported the existence of at least two types of human class II antigens. Here we present the results of experiments using restriction enzyme digestions and separation of DNA from individuals homozygous for the MHC followed by hybridization to human class II antigen alpha- and beta-chain cDNA probes. While the alpha-chain probe gave only a single hybridization band, the various beta-chain probes revealed a more complex pattern that is consistent with the existence of at least three separate beta-chain genes or pseudogenes in the human MHC.
Bacterial Proteins↗
Growth factor-binding proteases in the murine submaxillary gland: isolation of a cDNA clone.
The submaxillary gland of the adult male mouse contains a number of serine proteases, several of which are involved in the proteolytic processing of precursors to growth factors and other biologically active polypeptides. Here we report the isolation and identification of a cDNA clone corresponding to one of the proteases, the type B of the epidermal growth factor-binding protein. A pronounced sequence homology was found between the predicted activation peptide of this protease and the NH2-terminal extension of the nerve growth factor alpha subunit, suggesting that the latter protein has an uncleaved activation peptide attached to its NH2 terminus.
Amino Acid Sequence↗
Structure of class II transplantation antigens and their relationship to other molecules.
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Amino Acid Sequence↗
Subcellular localization in normal and vitamin A-deficient rat liver of vitamin A serum transport proteins, albumin, ceruloplasmin and class I major histocompatibility antigens.
The subcellular localization in rat liver cells of retinol-binding protein (RBP), prealbumin, ceruloplasmin, albumin, and class I transplantation antigen chains was investigated by radioimmunoassay determinations. The concentration of RBP was high in the rough and smooth endoplasmic reticulum (SER). The relative concentrations of prealbumin, ceruloplasmin and albumin were similar in the endoplasmic reticulum fractions and in the Golgi fraction. Neither of the proteins were found in significant amounts in the post-microsomal supernatant nor in the plasma membrane. The concentrations of the class I transplantation antigen chains were higher in the Golgi fraction than in the endoplasmic reticulum fractions. In the rough endoplasmic reticulum (RER) fraction ceruloplasmin and the class I antigens partially interact with high-molecular weight (MW) components, presumably membrane-bound glycosyltransferases. RBP, prealbumin and albumin seemed to be present in free form within the microsomal lumen. In vitamin A deficiency the RBP and to a lesser extent the prealbumin concentrations in the endoplasmic reticulum fractions were significantly increased, as compared to fractions from normal livers. This suggests that the presence of vitamin A is a prerequisite for the transport of RBP from the endoplasmic reticulum to the Golgi complex. The intracellular concentrations of albumin and ceruloplasmin were not significantly altered by vitamin A deficiency. In contrast, the amounts of the class I antigen heavy chains were found to be increased.
Animals↗
Structure of the murine immune response I-A beta locus: sequence of the I-A beta gene and an adjacent beta-chain second domain exon.
The murine major histocompatibility complex I region encodes two class II antigens, I-A and I-E. From a mouse spleen DNA cosmid library of the b haplotype, we isolated a clone containing the entire I-A beta gene and a separate exon encoding a beta-chain second domain (A beta 2). The A beta gene, encompassing more than 6 kb, is encoded by six exons corresponding to the different domains of the A beta polypeptide. The translated A beta amino acid sequence displays 73% homology to human DC beta chains; homologies to other subsets of human beta chains are lower, establishing that I-A corresponds structurally to DC. The A beta 2 exon is about 20 kb centromeric to the A beta gene. Its translated amino acid sequence includes all the conserved amino acids of other class II beta-chain second domains. It shows about 60% homology to each of three subsets of human beta chains available for comparison, and to the A beta chain. No A beta 2 first domain exon has been detected with A beta or DC beta probes.
Amino Acid Sequence↗
Detection of HLA-D/DR-related DNA polymorphism in HLA-D homozygous typing cells.
Sequences of different sizes are generated when DNA from homozygous HLA-Dw/DR typing cells are digested with restriction endonuclease and analyzed by hybridization with a HLA-D region class II antigen beta-chain cDNA probe. The patterns of hybridization were highly polymorphic but one endonuclease, BamHI, defined sequences unique to all HLA-Dw/DR specificities 1-8 except HLA-Dw/DR 2 and 6; however, these two specificities were resolved with the enzyme EcoRI. Digestion with other endonucleases such as Pst I results in patterns of restriction fragments that differ between homozygous typing cells of the same HLA-Dw/DR specificity. HLA-D region beta-chain probes permit HLA-D region genotyping at the DNA level and may allow detection of genes controlling the association of HLA specificities with a wide variety of diseases.
DNA↗
Exon-intron organization and complete nucleotide sequence of a human major histocompatibility antigen DC beta gene.
We have determined the complete nucleotide sequence of a human class II histocompatibility antigen DC beta gene. The gene spans more than 7 kilobases and contains five exons corresponding to the different domains of the DC beta polypeptide. The exon-intron organization is thus analogous to that of class II antigen alpha-chain genes, class I antigen heavy chain genes, and the constant parts of immunoglobulin genes, emphasizing further the evolutionary relationship among these molecules. The mature polypeptide deduced from the DC beta gene shows 93% and 88% homology, respectively, to sequences derived from two DC beta cDNA clones of other haplotypes. The allelic polymorphism of DC beta chains resides predominantly in the first extracellular domain, whereas the rest of the polypeptide is virtually constant. The exons of the DC beta gene display high homology to the corresponding exons of a murine I-A beta gene. Also, the introns show significant homology. The DC beta chains lack eight amino acids in the cytoplasmic tail, as compared to DR and I-A beta chains. This is probably due to a nonfunctional splice junction of DC beta genes, causing a separate cytoplasmic exon to be nonexpressed.
Amino Acid Sequence↗
cDNA clone for the human invariant gamma chain of class II histocompatibility antigens and its implications for the protein structure.
The invariant gamma chain is transitorily associated with class II histocompatibility antigens during intracellular transport. We have isolated and sequenced a cDNA clone corresponding to the human gamma chain. mRNA hybridizing to the cDNA clone translated into a 33,000-dalton chain that associated specifically with class II antigen alpha and beta chains. The gamma chain consists of 216 amino acids. The two N-linked carbohydrates are attached to asparagines 114 and 120. A continuous stretch of hydrophobic and neutral amino acids occurs in positions 31-56 from the NH2 terminus. This region seems to constitute the transmembrane portion of the polypeptide chain. The positions of the carbohydrate moieties and the putative transmembrane segment indicate that the NH2 terminus of the gamma chain resides on the cytoplasmic side of the membrane. Cell-free translations in conjunction with radiochemical amino acid sequence analyses suggest that the gamma chain lacks an NH2-terminal signal sequence.
Amino Acid Sequence↗
Ligand-dependent regulation of intracellular protein transport: effect of vitamin a on the secretion of the retinol-binding protein.
As a model of ligand-dependent protein secretion the biosynthesis, intracellular transport, and release of the retinol-binding protein (RBP) were studied in primary cultures of rat hepatocytes pulse-labeled with [35S]methionine. After various periods of chase RBP was isolated by immunoprecipitation and identified by SDS PAGE. Both normal and vitamin A-deficient hepatocytes synthesized RBP. The normal cells secreted the pulse-labeled RBP within 2 h. RBP synthesized by deficient cells was not secreted, and intracellular degradation of the protein appeared to be slow. Deficient cells could be induced to secrete RBP on the addition of retinol to the culture medium. This occurred also after protein synthesis had been blocked by cycloheximide. Since retinol induces the secretion of RBP, accumulated in the endoplasmic reticulum (ER), it seems reasonable to conclude that the transport of RBP from the ER to the Golgi complex is regulated by retinol.
Animals↗
Structure and tissue distribution of some retinoid-binding proteins.
Vitamin A has, apart from its function in the visual pigments, general effects on several organs. Early signs of vitamin A deficiency include keratinization of epithelia and hyperkeratosis of the skin. To elucidate a generalized function for vitamin A, we have taken the approach of tracing the vitamin from its storage site in the liver via its blood transport by the retinol-binding protein (RBP) to its uptake by susceptible cells. We have also examined the intracellular occurrence of vitamin A as regards its binding to specific receptor proteins. Here we summarize data on the amino acid sequences of several vitamin A-binding proteins. The finding that CRBP and CRABP, the two intracellular proteins, are homologous to each other, to a myelin protein, and to a fatty acid-binding protein may shed light on the functions of these proteins. Retinoic acid, which binds to CRABP but not CRBP, induces differentiation of teratocarcinoma cells. This is accompanied by a lowering of the CRABP concentration, an increase of the CRBP level, and an increase in the uptake of retinol from RBP. The epidermis contains both CRBP and CRABP, and their distributions are rather similar. However, in contrast to CRBP, CRABP is most abundant in cells lining the hair follicles. CRBP occurs in greatest relative amounts in the outer layers of the epidermis. Since techniques have been developed to measure CRBP and CRABP, normal and disease-affected skin may now be explored as to quantity and cellular distribution of the retinoid-binding proteins.
Amino Acid Sequence↗
Partial amino-acid sequence of the epidermal growth-factor-binding protein.
The partial amino acid sequence of the epidermal growth-factor-binding protein was determined. Residues in 108 unique positions, corresponding to 45% of the molecule, were identified. The protein is a serine protease, closely related to the nerve growth factor gamma subunit. It is suggested that the epidermal growth-factor-binding protein, like other serine protease, is synthesized as a single polypeptide chain which undergoes limited endoproteolysis. The isolated material also contained minor amounts of a second serine protease. This protease is closely related to the epidermal growth-factor-binding protein, differing from it in 7 out of the 45 amino acid positions available for comparison. The latter protease may be identical to the previously described protease A.
Amino Acid Sequence↗
Purification and partial amino acid sequence of papain-solubilized class II transplantation antigens.
Papain-solubilized human class II (HLA-DR) antigens have been purified from cadaveric spleens by ion-exchange chromatography, gel chromatography, and immunosorbent purification. The isolated papain-solubilized antigens comprised two subunits with apparent molecular weights of 23 000 and 30 000, respectively. The circular dichroism spectrum for the isolated class II antigens was similar to spectra recorded for HLA-A, -B, and -C antigens, immunoglobulins, and immunoglobulin fragments. Thus, class II antigens contain a considerable amount of beta structure. The small subunit (beta chain) exhibited extensive charge heterogeneity on two-dimensional isoelectric focusing polyacrylamide gel electrophoresis, whereas the large subunit (alpha chain) was more homogeneous. The structural heterogeneity of beta chains remained after neuraminidase treatment. The NH2-terminal amino acid sequence of the beta chains displayed multiple residues in several positions in accordance with the genetic polymorphism displayed by this chain. The alpha chain also displayed multiple residues in some positions, suggesting either that some of the genetic polymorphism of the class II antigens may be endowed in this chain or that multiple loci control the expression of several alpha chains. Papain-solubilized class II antigen subunits were homologous in their amino acid sequences with HLA-DR antigens of defined antigenic specificity as well as with murine I-E/C antigens.
Amino Acid Sequence↗
Alpha chain of HLA-DR transplantation antigens is a member of the same protein superfamily as the immunoglobulins.
Four cDNA clones, pDR-alpha-1, pDR-alpha-2, pDR-alpha-3 and pDR-alpha-4, corresponding to the alpha chain of HLA-DR antigens, have been sequenced. Restriction maps and sequences suggest that all clones are identical apart from a single-base substitution present in pDR-alpha-1. Amino acid sequence data, together with the nucleotide sequence data, allowed the complete amino acid sequence to be predicted. The alpha chain is composed of 229 amino acids, of which 191 are exposed on the outside of the plasma membrane. The membrane-embedded portion of the chain consists of 23 hydrophobic amino acids. The succeeding 15 amino acids form the cytoplasmically localized hydrophilic tail. The extracellular portion, with carbohydrate moieties linked to Asn78 and Asn118, seems to be organized into two domains. The second domain, which contains the only disulfide bond of the alpha chain, displays amino acid sequence homology to immunoglobulin constant regions, to the second domain of the beta chain of a class II antigen, to the third domain of heavy chains of class I antigens and to beta 2-microglobulin. Thus the subunits of immunoglobulins, class I antigens and class II antigens are related evolutionarily.
Amino Acid Sequence↗