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Packing Density of the Erythropoietin Receptor Transmembrane Domain Correlates with Amplification of Biological Responses

Becker, V; Sengupta, D; Ketteler, R; Ullmann, GM; Smith, JC; Klingmuller, U; (2008) Packing Density of the Erythropoietin Receptor Transmembrane Domain Correlates with Amplification of Biological Responses. BIOCHEMISTRY-US , 47 (45) 11771 - 11782. 10.1021/bi801425e.

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Abstract

The formation of signal-promoting dimeric or oligomeric receptor complexes at the cell surface is modulated by self-interaction of their transmembrane (TM) domains. To address the importance of TM domain packing density for receptor functionality, we examined a set of asparagine mutants in the TM domain of the erythropoietin receptor (EpoR). We identified EpoR-T242N as a receptor variant that is present at the cell surface similar to wild-type EpoR but lacks visible localization in vesicle-like structures and is impaired in efficient activation of specific signaling cascades. Analysis by a molecular modeling approach indicated an increased interhelical distance for the EpoR-T242N TM dimer. By employing the model, we designed additional mutants with increased or decreased packing volume and confirmed a correlation between packing volume and biological responsiveness. These results propose that the packing density of the TM domain provides a novel layer for fine-tuned regulation of signal transduction and cellular decisions.

Type: Article
Title: Packing Density of the Erythropoietin Receptor Transmembrane Domain Correlates with Amplification of Biological Responses
DOI: 10.1021/bi801425e
Keywords: PRIMARY FAMILIAL POLYCYTHEMIA, SIGNAL-TRANSDUCTION, MEMBRANE-PROTEINS, PROGENITOR CELLS, POINT MUTATION, DIMERIZATION, ACTIVATION, OLIGOMERIZATION, GENE, ERYTHROCYTOSIS
URI: http://discovery.ucl.ac.uk/id/eprint/1308074
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