The β2-microglobulin gene is on chromosome 15 and not in the HL-A region

Goodfellow, Peter N.; Jones, Eric J.; Heyningen, Veronica van; Solomon, Ellen; Bobrow, Martin; Miggiano, V.; Bodmer, Walter F.

doi:10.1038/254267a0

Cited by 267 publications

(81 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The advantage of this approach is that interactions normally occurring inside the cell, and hence not directly amenable to experimental manipulation, can be reconstructed directly on the topologically equivalent external face of the microsomal vesicle. For example, data from cellular studies of human (35) and mouse (36) tumor lines that do not express-HLA or H-2 antigens indicate that expression of 132-microglobulin is essential for the expression of the major histocompatibility antigens (37)(38). It should be possible to examine the need for coexpression of H-2 antigens and 32-microglobulin and the relative rates of synthesis of the integral membrane proteins and /32-microglobulin in detail in this system.…”

Section: Discussionmentioning

confidence: 99%

Cell-free synthesis and segregation of beta 2-microglobulin.

Lingappa¹,

Cunningham²,

Jazwinski³

et al. 1979

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

#2-Microglobulin has been synthesized in vitro by using a rabbit reticulocyte lysate system and mRNA from the mouse tumor cell line EL4. The molecule is synthesized as a precursor with an NH2-terminal extension of 19 amino acids: Ser-X-Ser-Val-X-Leu-Val-Phe-Leu-Val-Leu-Val-Ser-Leu-X-Gly-Leu-Tyr-X. The 132-Microglobulin is a low molecular weight protein (1) that is found on the surfaces of nearly all cells where it is associated with the major histocompatibility antigens, such as the H-2 antigens in mice and the HLA antigens in man (2-5), and related molecules (6-8). It is not an integral membrane protein in that it does not span the membrane and is not inserted into the lipid bilayer. It is closely, but noncovalently, associated with integral membrane proteins and can be removed by agents such as 3 M thiocyanate. By these criteria, it is one type of peripheral membrane protein (9). The molecule is also found free in various biological fluids including urine, serum, amniotic fluid, milk, and seminal fluid (10). Initially discovered in man, f2-microglobulin is probably present in nearly all vertebrate species (10, 11), and one such molecule from cow's milk has recently been crystallized (12). A distinguishing feature of this protein is that it resembles the constant region domains (CL, CHI, CH2, and CH3) of immunoglobulins in overall structure (13), in amino acid sequence (14-16), and in the arrangement of its disulfide bond (16). The functions of f3rmicroglobulin and the cell surface antigens with which it is associated are unknown. One approach to elucidating the functions of these antigens might be to construct cell-free systems in which molecular interactions could be dissected.The "signal hypothesis" for the segregation of certain classes of newly synthesized proteins (17) has been confirmed in the case of a large number of secretory proteins (18-21) and several integral membrane proteins (22-24). For both classes, it has been demonstrated that common early events mediate insertion and chain transfer across the microsomal membrane via a ribosome-membrane junction (23). Integral membrane proteins, however, have been proposed to contain a "stop transfer" sequence whose function is to abrogate the ribosome-membrane junction, dissolve the tunnel, and deposit the nascent chain in a correct transmembrane orientation (23,25).Cell surface proteins whose interactions with the membrane do not involve integration within the hydrophobic regions of the lipid bilayer would be expected to follow the general biosynthetic plan of secretory proteins. f2-Microglobulin offers a suitable system for in vitro studies of the biosynthesis of this class of membrane proteins.As a first step toward construction of a cell-free system for the study of the coordinate synthesis of 32-microglobulin and its associated integral membrane protein (H-2 or HLA antigens), we present here data on the biosynthesis of 12-microglobulin including its synthesis, segregation, and proteolytic processing. Our results demonstrate that 32-microglob...

show abstract

Section: Discussionmentioning

confidence: 99%

Cell-free synthesis and segregation of beta 2-microglobulin.

Lingappa¹,

Cunningham²,

Jazwinski³

et al. 1979

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…a polymorphic heavy chain (M r 40 000-45 000), encoded within the major histocompatibility complex (MHC) on the short arm of chromosome 6, and an invariant light chain (M r 12 000), beta-2 microglobulin (B2m), encoded on chromosome 15 (Goodfellow et al 1975, Grey et al 1973, Coligan et al 1981. Each heavy chain is composed of three extracellular domains (c~1, ~2, ~3) of about 90 amino acids, a hydrophobic transmembrane segment, and a hydrophilic cytoplasmic region.…”

Section: Introductionmentioning

confidence: 99%

Allelic variation in HLA-B and HLA-C sequences and the evolution of the HLA-B alleles

et al. 1989

View full text Add to dashboard Cite

Abstract. Several new HLA-B (B8, B51, Bw62)-andHLA-C (Cw6, Cw7)-specific genes were isolated either as genomic cosmid or cDNA clones to study the diversity of HLA antigens. The allele specificities were identified by sequence analysis in comparison with published HLA-B and -C sequences, by transfection experiments, and Southern and northern blot analysis using oligonucleotide probes. Comparison of the classical HLA-A, -B, and -C sequences reveals that allele-specific substitutions seem to be rare events. HLA-B51 codes only for one allelespecific residue: arginine at position 81 located on the cd helix, pointing toward the antigen binding site. HLA-B8 contains an acidic substitution in amino acid position 9 on the first central/3 sheet which might affect antigen binding capacity, perhaps in combination with the rare replacement at position 67 (F) on the c~l helix. HLA-B8 shows greatest homology to HLA-Bw42, -Bw41, -B7, and -Bw60 antigens, all of which lack the conserved restriction sites Pst I at position 180 and Sac I at position 131. Both sites associated with amino acid replacements seem to be genetic markers of an evolutionary split of the HLA-B alleles, which is also observed in the leader sequences. HLA-Cw7 shows 98% sequence identity to the JY328 gene. In general, the HLA-C alleles display lower levels of variability in the highly polymorphic regions of the c~ 1 and c~2 domains, and have more distinct patterns of locusspecific residues in the transmembrane and cytoplasmic domains. Thus we propose a more recent origin for the HLA-C locus.

show abstract

“…8 -11 b2m, a highly conserved gene mapping to the long (q) arm of chromosome 15 at band q22, encodes a protein of 12 kDa (light chain) that associates with the polymorphic HLA class I heavy chains. 12 The intracellular assembly of both components is a prerequisite for the surface presentation of HLA class I antigens. Total loss of antigen expression is dependent on mutational events involving both copies of the b2m gene.…”

mentioning

confidence: 99%

Complete loss of HLA class I antigen expression on melanoma cells: A result of successive mutational events

Paschen

Méndez

Jiménez

et al. 2002

Intl Journal of Cancer

View full text Add to dashboard Cite

Alterations in the surface expression of HLA class I molecules have been described as a strategy of tumors to evade recognition by cytotoxic T cells. We detected complete loss of HLA class I antigen presentation for 2 tumor cell lines from 1 melanoma patient, the first originated from a regional lymph node lesion diagnosed simultaneously with the primary tumor and the second established 8 months later from a metastatic pleural effusion sample. Antigen presentation was not inducible with IFN-␥ but could be restored after transfection of tumor cells with b2m cDNA, indicating a defect in b2m expression. Analysis of the nature of this defect revealed that it originated from at least 2 mutational events affecting both copies of the b2m gene: a microdeletion of 498 bp in one b2m gene, including its entire exon 1, and a macrodeletion involving the entire copy of the second b2m gene. Microsatellite analysis pointed to the macrodeletion by demonstrating LOH for several specific markers on the long arm (q) of chromosome 15. Structural imbalance of 15q was verified by FISH. FISH studies also indicated the coexistence of a structurally abnormal variant of chromosome 15q with 2 apparently entire chromosomes 15q harboring the homozygous b2m microdeletion. Block of b2m expression in tumor cells builds a barrier to immunotherapy of cancer patients, and its early incidence should be of major consideration in the development and design of immunotherapeutic strategies.

show abstract

The β2-microglobulin gene is on chromosome 15 and not in the HL-A region

Cited by 267 publications

References 27 publications

Cell-free synthesis and segregation of beta 2-microglobulin.

Cell-free synthesis and segregation of beta 2-microglobulin.

Allelic variation in HLA-B and HLA-C sequences and the evolution of the HLA-B alleles

Complete loss of HLA class I antigen expression on melanoma cells: A result of successive mutational events

Contact Info

Product

Resources

About