engleski

Sorting of nonconformed and misfolded MHC class I molecules into lipid rafts

SORTING OF NONCONFORMED AND MISSFOLDED MHC CLASS I MOLECULES INTO LIPID RAFTS Lučin P., Mahmutefendić H., Kučić N., and Blagojević G. Department of Physiology and Immunology, Medical Faculty of the University of Rijeka, Rijeka, Croatia Surface glycoproteins are a constitutive part of the cell membrane and their equilibrium at the cell surface is achieved by a balance between new synthesis and regulated processes of their removal from the cell surface, such as internalisation by endocytosis, and the subsequent degradation. Surface glycoproteins can be internalised constitutively (spontaneously) and their internalisation can be induced by binding of a ligand, ie. antibody or other external molecule. Endocytic mechanisms of cellular glycoproteins are different, but mostly involve two types: regulated internalisation (clathrin endocytosis and lipid-rafts mediated endocytosis) and fluid phase endocytosis (a bulk pathway). MHC class I molecules are highly polymorphic surface glycoproteins that are involved in immune recognition. A majority of the class I MHC protein molecules are present at the cell surface as dimers of two noncovalently associated chains, a transmembrane H chain and  2-microglobulin. In this form they strongly associate with a broad spectrum of peptides which are presented to T lyphocytes. A smaller fraction of the MHC molecules on the cell surface exist as functionally inactive  2m-free H chains believed to be formed by the dissociation of  2m and peptide from the previously cell surface-expressed heterodimers. This form does not bind peptides and is recognized by mAbs that recognize denatured H chains. The biological role of these  2m-free class I H chains is not clear. Endocytosis of MHC class I molecules was studied under conditions of spontaneous internalisation and induced internalisation after binding of specific monoclonal antibodies. MHC class I alleles differs regarding their stability, kinetics, and the way of internalisation and degradation. Kd and Dd molecules are more stable than Ld molecules and have longer surface half-life. Internalisation mechanism of fully conformed Ld molecules (full) differs from internalisation of non-conformed Ld molecules (empty). A majority of internalised MHC class I molecules are recycled, and only a smaller part is degraded. In this study we demonstrate that nonconformed and missfolded Ld and Dd molecules at the cell surface are sorted into detergent insoluble membrane domains, rich in cholesterol (lipid rafts) for endocytosis.

lipid rafts; MHC class I molecules; protein sorting

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