The cytoplasmic domain of the H-2Ld class I major histocompatibility complex molecule is differentially accessible to immunological and biochemical probes during transport to the cell surface.

Capps, G G; Zúñiga, Martha C.

doi:10.1016/s0021-9258(19)36919-4

Cited by 10 publications

(5 citation statements)

References 35 publications

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“…Dimerization may occur in different alleles at different time points depending on the nature of the activating factor, implying that the dimerization may differ under different pathological conditions. The functional potential of these homo- and heterodimers requires extensive experimental investigation, further developing the work conducted by previous investigators [ 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 ].…”

Section: Current Concepts Concerning Oligomerization Of Face-2mentioning

confidence: 97%

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Cell Surface B2m-Free Human Leukocyte Antigen (HLA) Monomers and Dimers: Are They Neo-HLA Class and Proto-HLA?

Ravindranath

Selvan

et al. 2023

Biomolecules

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Cell surface HLA-I molecules (Face-1) consist of a polypeptide heavy chain (HC) with two groove domains (G domain) and one constant domain (C-domain) as well as a light chain, B2-microglobulin (B2m). However, HCs can also independently emerge unfolded on the cell surface without peptides as B2m-free HC monomers (Face-2), B2m-free HC homodimers (Face 3), and B2m-free HC heterodimers (Face-4). The transport of these HLA variants from ER to the cell surface was confirmed by antiviral antibiotics that arrest the release of newly synthesized proteins from the ER. Face-2 occurs at low levels on the normal cell surface of the lung, bronchi, epidermis, esophagus, breast, stomach, ilium, colorectum, gall bladder, urinary bladder, seminal vesicles ovarian epithelia, endometrium, thymus, spleen, and lymphocytes. They are upregulated on immune cells upon activation by proinflammatory cytokines, anti-CD3 antibodies, antibiotics (e.g., ionomycin), phytohemagglutinin, retinoic acid, and phorbol myristate acetate. Their density on the cell surface remains high as long as the cells remain in an activated state. After activation-induced upregulation, the Face-2 molecules undergo homo- and hetero-dimerization (Face-3 and Face-4). Alterations in the redox environment promote dimerization. Heterodimerization can occur among and between the alleles of different haplotypes. The glycosylation of these variants differ from that of Face-1, and they may occur with bound exogenous peptides. Spontaneous arthritis occurs in HLA-B27+ mice lacking B2m (HLA-B27+ B2m−/−) but not in HLA-B27+ B2m+/− mice. The mice with HLA-B27 in Face-2 spontaneous configuration develop symptoms such as changes in nails and joints, hair loss, and swelling in paws, leading to ankyloses. Anti-HC-specific mAbs delay disease development. Some HLA-I polyreactive mAbs (MEM series) used for immunostaining confirm the existence of B2m-free variants in several cancer cells. The upregulation of Face-2 in human cancers occurs concomitantly with the downregulation of intact HLAs (Face-1). The HLA monomeric and dimeric variants interact with inhibitory and activating ligands (e.g., KIR), growth factors, cytokines, and neurotransmitters. Similarities in the amino acid sequences of the HLA-I variants and HLA-II β-chain suggest that Face-2 could be the progenitor of both HLA classes. These findings may support the recognition of these variants as a neo-HLA class and proto-HLA.

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Section: Current Concepts Concerning Oligomerization Of Face-2mentioning

confidence: 97%

“…The dimerization of HLA HCs was investigated on H-2L d and H-2D b MHC class I molecules of the mouse by Capps and Zuniga [ 129 , 130 ]. They generated antiserum against a synthetic peptide corresponding to a portion of the cytoplasmic domains of the HCs of H-2L d and H-2D b .…”

Section: Current Concepts Concerning Oligomerization Of Face-2mentioning

confidence: 99%

Cell Surface B2m-Free Human Leukocyte Antigen (HLA) Monomers and Dimers: Are They Neo-HLA Class and Proto-HLA?

Ravindranath

Selvan

et al. 2023

Biomolecules

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“…Ensuing studies showed that pSer335 abrogated the binding of antibodies specific for a conserved sequence present in the cytoplasmic domain of H-2 class I molecules. These studies revealed that the antibodies specifically recognized cell surface H-2 class I molecules not associated with β2m, that is, open conformers [ 10 , 11 , 12 ]. Similar studies using human cell lines showed that the dissociation of β2m from cell surface HLA-I αHCs correlated with acquiring a cryptic epitope in the cytoplasmic domain, likely resulting from de-phosphorylation of Ser335 [ 13 ].…”

Section: Open Mhc-i Conformers: Structure Origin and The Search For A Physiological Functionmentioning

confidence: 99%

“…These PDZ sequences regulate protein localization and the formation of scaffolds involved in cell–cell contact at immunological and neuronal synapses [ 204 , 205 ]. Notably, these PDZ motifs contain the conserved Tyr320 and Ser335 residues, targets of in vivo phosphorylation/de-phosphorylation, post-translational modifications that identify cell surface open and closed conformers [ 5 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ].…”

Section: Open Mhc-i Conformers: Unforeseen Modulators Of Neuronal Development and Synaptic Plasticity?mentioning

confidence: 99%

“…The phosphorylation status may allow membrane movement, localization and trafficking [ 5 ]. Thus, based on the current knowledge, pSer335 and pTyr320 may be considered as surrogate biomarkers of closed and open conformers, respectively (see [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ], and text). ( C ) The open conformers formed at the plasma membrane of metabolically active cells may self cis-associate originating αHC homodimers, or hetero cis-associate originating αHC heterodimers (not shown, see Section 4 ).…”

Section: Figurementioning

confidence: 99%

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Open MHC Class I Conformers: A Look through the Looking Glass

Arosa

Esgalhado

Reste-Ferreira

et al. 2021

IJMS

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Studies carried out during the last few decades have consistently shown that cell surface MHC class I (MHC-I) molecules are endowed with functions unrelated with antigen presentation. These include cis–trans-interactions with inhibitory and activating KIR and LILR, and cis-interactions with receptors for hormones, growth factors, cytokines, and neurotransmitters. The mounting body of evidence indicates that these non-immunological MHC-I functions impact clinical and biomedical settings, including autoimmune responses, tumor escape, transplantation, and neuronal development. Notably, most of these functions appear to rely on the presence of hematopoietic and non-hematopoietic cells of heavy chains not associated with β2m and the peptide at the plasma membrane; these are known as open MHC-I conformers. Nowadays, open conformers are viewed as functional cis-trans structures capable of establishing physical associations with themselves, with other surface receptors, and being shed into the extracellular milieu. We review past and recent developments, strengthening the view that open conformers are multifunctional structures capable of fine-tuning cell signaling, growth, differentiation, and cell communication.

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Traffic control of completely assembled MHC class I molecules beyond the endoplasmic reticulum

Joyce

1997

Journal of Molecular Biology

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The cytoplasmic domain of the H-2Ld class I major histocompatibility complex molecule is differentially accessible to immunological and biochemical probes during transport to the cell surface.

Cited by 10 publications

References 35 publications

Cell Surface B2m-Free Human Leukocyte Antigen (HLA) Monomers and Dimers: Are They Neo-HLA Class and Proto-HLA?

Cell Surface B2m-Free Human Leukocyte Antigen (HLA) Monomers and Dimers: Are They Neo-HLA Class and Proto-HLA?

Open MHC Class I Conformers: A Look through the Looking Glass

Traffic control of completely assembled MHC class I molecules beyond the endoplasmic reticulum

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